EP3452466A1 - Heterocyclic triazole compounds as agonists of the apj receptor - Google Patents
Heterocyclic triazole compounds as agonists of the apj receptorInfo
- Publication number
- EP3452466A1 EP3452466A1 EP17733197.2A EP17733197A EP3452466A1 EP 3452466 A1 EP3452466 A1 EP 3452466A1 EP 17733197 A EP17733197 A EP 17733197A EP 3452466 A1 EP3452466 A1 EP 3452466A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- triazol
- dimethoxyphenyl
- sulfonamide
- pyrimidinyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- -1 Heterocyclic triazole compounds Chemical class 0.000 title claims description 99
- 239000000556 agonist Substances 0.000 title abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 546
- 150000001875 compounds Chemical class 0.000 claims abstract description 471
- 239000000203 mixture Substances 0.000 claims abstract description 293
- 230000002526 effect on cardiovascular system Effects 0.000 claims abstract description 79
- 108091008803 APLNR Proteins 0.000 claims abstract description 29
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 461
- 125000000623 heterocyclic group Chemical group 0.000 claims description 328
- 125000005842 heteroatom Chemical group 0.000 claims description 239
- 125000001424 substituent group Chemical group 0.000 claims description 235
- 229910052760 oxygen Inorganic materials 0.000 claims description 189
- 238000000034 method Methods 0.000 claims description 160
- 125000001072 heteroaryl group Chemical group 0.000 claims description 130
- 125000002950 monocyclic group Chemical group 0.000 claims description 114
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 84
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 83
- 125000003118 aryl group Chemical group 0.000 claims description 76
- 229920006395 saturated elastomer Polymers 0.000 claims description 73
- 125000004432 carbon atom Chemical group C* 0.000 claims description 64
- 125000002619 bicyclic group Chemical group 0.000 claims description 60
- 239000003814 drug Substances 0.000 claims description 60
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 57
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 57
- 229940124597 therapeutic agent Drugs 0.000 claims description 53
- 229940125364 angiotensin receptor blocker Drugs 0.000 claims description 51
- 239000008194 pharmaceutical composition Substances 0.000 claims description 49
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 45
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 41
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 36
- 239000003112 inhibitor Substances 0.000 claims description 34
- 102000003729 Neprilysin Human genes 0.000 claims description 32
- 108090000028 Neprilysin Proteins 0.000 claims description 32
- 229910052799 carbon Inorganic materials 0.000 claims description 31
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 30
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 28
- 125000000217 alkyl group Chemical group 0.000 claims description 28
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 27
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims description 27
- 238000010438 heat treatment Methods 0.000 claims description 25
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- 239000002253 acid Substances 0.000 claims description 23
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 21
- 229910052757 nitrogen Inorganic materials 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 20
- 206010019280 Heart failures Diseases 0.000 claims description 19
- 230000000747 cardiac effect Effects 0.000 claims description 19
- 230000001684 chronic effect Effects 0.000 claims description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 18
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 18
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 17
- 206010020772 Hypertension Diseases 0.000 claims description 16
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 16
- 150000004292 cyclic ethers Chemical class 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 125000004076 pyridyl group Chemical group 0.000 claims description 15
- 229940127291 Calcium channel antagonist Drugs 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 150000001204 N-oxides Chemical class 0.000 claims description 14
- 239000002160 alpha blocker Substances 0.000 claims description 14
- 239000002876 beta blocker Substances 0.000 claims description 14
- 229940097320 beta blocking agent Drugs 0.000 claims description 14
- 239000000480 calcium channel blocker Substances 0.000 claims description 14
- 239000002934 diuretic Substances 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 13
- 229940098712 Myosin activator Drugs 0.000 claims description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
- 206010012601 diabetes mellitus Diseases 0.000 claims description 12
- 230000001882 diuretic effect Effects 0.000 claims description 12
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 12
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 11
- 208000003037 Diastolic Heart Failure Diseases 0.000 claims description 11
- 208000008589 Obesity Diseases 0.000 claims description 11
- 208000008253 Systolic Heart Failure Diseases 0.000 claims description 11
- 208000038003 heart failure with preserved ejection fraction Diseases 0.000 claims description 11
- 208000038002 heart failure with reduced ejection fraction Diseases 0.000 claims description 11
- 235000020824 obesity Nutrition 0.000 claims description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 10
- CXUYQCCFOFHWNA-MRXNPFEDSA-N 2-(4-chlorophenyl)-N-[4-(2,6-dimethoxyphenyl)-5-[(3S)-oxolan-3-yl]-1,2,4-triazol-3-yl]ethanesulfonamide Chemical compound ClC1=CC=C(C=C1)CCS(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@H]1COCC1 CXUYQCCFOFHWNA-MRXNPFEDSA-N 0.000 claims description 10
- 206010007556 Cardiac failure acute Diseases 0.000 claims description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- 230000001965 increasing effect Effects 0.000 claims description 10
- 125000003386 piperidinyl group Chemical group 0.000 claims description 10
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 10
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 10
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 9
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 9
- 208000020832 chronic kidney disease Diseases 0.000 claims description 9
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 9
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 8
- 230000003213 activating effect Effects 0.000 claims description 8
- 125000000532 dioxanyl group Chemical group 0.000 claims description 8
- 229910000000 metal hydroxide Inorganic materials 0.000 claims description 8
- 150000004692 metal hydroxides Chemical class 0.000 claims description 8
- 125000003566 oxetanyl group Chemical group 0.000 claims description 8
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 8
- CXUYQCCFOFHWNA-INIZCTEOSA-N 2-(4-chlorophenyl)-N-[4-(2,6-dimethoxyphenyl)-5-[(3R)-oxolan-3-yl]-1,2,4-triazol-3-yl]ethanesulfonamide Chemical compound ClC1=CC=C(C=C1)CCS(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@@H]1COCC1 CXUYQCCFOFHWNA-INIZCTEOSA-N 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 238000011269 treatment regimen Methods 0.000 claims description 6
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 5
- PTNMUXPIZNNNNU-QMIHWGKISA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(2R)-oxan-2-yl]-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@@H]1OCCCC1)OC PTNMUXPIZNNNNU-QMIHWGKISA-N 0.000 claims description 4
- FJJSHJFUPWNUNO-IRWQIABSSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(2S)-1,4-dioxan-2-yl]-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@@H]1OCCOC1)OC FJJSHJFUPWNUNO-IRWQIABSSA-N 0.000 claims description 4
- PTNMUXPIZNNNNU-DCPHZVHLSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(2S)-oxan-2-yl]-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@H]1OCCCC1)OC PTNMUXPIZNNNNU-DCPHZVHLSA-N 0.000 claims description 4
- JRZJKXDZGZVHAF-BJJXKVORSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-[4-(4,6-dimethoxypyrimidin-5-yl)-5-[(2R)-5,5-dimethyloxolan-2-yl]-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C=1C(=NC=NC=1OC)OC)[C@@H]1OC(CC1)(C)C)OC JRZJKXDZGZVHAF-BJJXKVORSA-N 0.000 claims description 4
- JRZJKXDZGZVHAF-NOLJZWGESA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-[4-(4,6-dimethoxypyrimidin-5-yl)-5-[(2S)-5,5-dimethyloxolan-2-yl]-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C=1C(=NC=NC=1OC)OC)[C@H]1OC(CC1)(C)C)OC JRZJKXDZGZVHAF-NOLJZWGESA-N 0.000 claims description 4
- NEGKVGKUVYAGIE-QTGUNEKASA-N (1S,2S)-N-[4-(2,6-dimethoxyphenyl)-5-[(2R)-5,5-dimethyloxolan-2-yl]-1,2,4-triazol-3-yl]-1-(5-methylpyrimidin-2-yl)-1-propan-2-yloxypropane-2-sulfonamide Chemical compound COC1=C(C(=CC=C1)OC)N1C(=NN=C1[C@@H]1OC(CC1)(C)C)NS(=O)(=O)[C@H]([C@H](C1=NC=C(C=N1)C)OC(C)C)C NEGKVGKUVYAGIE-QTGUNEKASA-N 0.000 claims description 4
- NEGKVGKUVYAGIE-AVCGJXAMSA-N (1S,2S)-N-[4-(2,6-dimethoxyphenyl)-5-[(2S)-5,5-dimethyloxolan-2-yl]-1,2,4-triazol-3-yl]-1-(5-methylpyrimidin-2-yl)-1-propan-2-yloxypropane-2-sulfonamide Chemical compound COC1=C(C(=CC=C1)OC)N1C(=NN=C1[C@H]1OC(CC1)(C)C)NS(=O)(=O)[C@H]([C@H](C1=NC=C(C=N1)C)OC(C)C)C NEGKVGKUVYAGIE-AVCGJXAMSA-N 0.000 claims description 4
- DGEREDFOSTVFRK-LZLYRXPVSA-N (1S,2S)-N-[4-(4,6-dimethoxypyrimidin-5-yl)-5-[(2R)-oxolan-2-yl]-1,2,4-triazol-3-yl]-1-(5-methylpyrimidin-2-yl)-1-propan-2-yloxypropane-2-sulfonamide Chemical compound COC1=NC=NC(=C1N1C(=NN=C1[C@@H]1OCCC1)NS(=O)(=O)[C@H]([C@H](C1=NC=C(C=N1)C)OC(C)C)C)OC DGEREDFOSTVFRK-LZLYRXPVSA-N 0.000 claims description 4
- DGEREDFOSTVFRK-XYJFISCASA-N (1S,2S)-N-[4-(4,6-dimethoxypyrimidin-5-yl)-5-[(2S)-oxolan-2-yl]-1,2,4-triazol-3-yl]-1-(5-methylpyrimidin-2-yl)-1-propan-2-yloxypropane-2-sulfonamide Chemical compound COC1=NC=NC(=C1N1C(=NN=C1[C@H]1OCCC1)NS(=O)(=O)[C@H]([C@H](C1=NC=C(C=N1)C)OC(C)C)C)OC DGEREDFOSTVFRK-XYJFISCASA-N 0.000 claims description 4
- GSXUHLGBQGDOQU-ZIAGYGMSSA-N (2R)-N-[4-(2,6-dimethoxyphenyl)-5-[(3S)-oxolan-3-yl]-1,2,4-triazol-3-yl]-1-(5-fluoropyrimidin-2-yl)propane-2-sulfonamide Chemical compound COC1=C(C(=CC=C1)OC)N1C(=NN=C1[C@H]1COCC1)NS(=O)(=O)[C@@H](CC1=NC=C(C=N1)F)C GSXUHLGBQGDOQU-ZIAGYGMSSA-N 0.000 claims description 4
- GSXUHLGBQGDOQU-KBPBESRZSA-N (2S)-N-[4-(2,6-dimethoxyphenyl)-5-[(3R)-oxolan-3-yl]-1,2,4-triazol-3-yl]-1-(5-fluoropyrimidin-2-yl)propane-2-sulfonamide Chemical compound COC1=C(C(=CC=C1)OC)N1C(=NN=C1[C@@H]1COCC1)NS(=O)(=O)[C@H](CC1=NC=C(C=N1)F)C GSXUHLGBQGDOQU-KBPBESRZSA-N 0.000 claims description 4
- GSXUHLGBQGDOQU-UONOGXRCSA-N (2S)-N-[4-(2,6-dimethoxyphenyl)-5-[(3S)-oxolan-3-yl]-1,2,4-triazol-3-yl]-1-(5-fluoropyrimidin-2-yl)propane-2-sulfonamide Chemical compound COC1=C(C(=CC=C1)OC)N1C(=NN=C1[C@H]1COCC1)NS(=O)(=O)[C@H](CC1=NC=C(C=N1)F)C GSXUHLGBQGDOQU-UONOGXRCSA-N 0.000 claims description 4
- BQYDXKYLGQKPAB-DEYYWGMASA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(2R)-1,4-dioxan-2-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@H]1OCCOC1)C BQYDXKYLGQKPAB-DEYYWGMASA-N 0.000 claims description 4
- BQYDXKYLGQKPAB-SUNYJGFJSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(2S)-1,4-dioxan-2-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@@H]1OCCOC1)C BQYDXKYLGQKPAB-SUNYJGFJSA-N 0.000 claims description 4
- QIBDMBGERPDXOG-DCGLDWPTSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(2S)-oxetan-2-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@H]1OCC1)C QIBDMBGERPDXOG-DCGLDWPTSA-N 0.000 claims description 4
- AMAXYHCDGOXFOP-KKUMJFAQSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(3R)-oxolan-3-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@@H]1COCC1)C AMAXYHCDGOXFOP-KKUMJFAQSA-N 0.000 claims description 4
- AMAXYHCDGOXFOP-SOUVJXGZSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(3S)-oxolan-3-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@H]1COCC1)C AMAXYHCDGOXFOP-SOUVJXGZSA-N 0.000 claims description 4
- GIIOLTWGWQXHKG-OBJOEFQTSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(4,6-dimethoxypyrimidin-5-yl)-5-[(2R)-1,4-dioxan-2-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C=1C(=NC=NC=1OC)OC)[C@H]1OCCOC1)C GIIOLTWGWQXHKG-OBJOEFQTSA-N 0.000 claims description 4
- GIIOLTWGWQXHKG-SGMGOOAPSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(4,6-dimethoxypyrimidin-5-yl)-5-[(2S)-1,4-dioxan-2-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C=1C(=NC=NC=1OC)OC)[C@@H]1OCCOC1)C GIIOLTWGWQXHKG-SGMGOOAPSA-N 0.000 claims description 4
- BPYZHXRJLIJAOG-TXPKVOOTSA-N (2S,3R)-N-[4-(2,6-dimethoxyphenyl)-5-[(2R)-oxolan-2-yl]-1,2,4-triazol-3-yl]-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide Chemical compound COC1=C(C(=CC=C1)OC)N1C(=NN=C1[C@@H]1OCCC1)NS(=O)(=O)[C@@H](C)[C@H](C)C1=NC=C(C=N1)C BPYZHXRJLIJAOG-TXPKVOOTSA-N 0.000 claims description 4
- BPYZHXRJLIJAOG-BXWFABGCSA-N (2S,3R)-N-[4-(2,6-dimethoxyphenyl)-5-[(2S)-oxolan-2-yl]-1,2,4-triazol-3-yl]-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide Chemical compound COC1=C(C(=CC=C1)OC)N1C(=NN=C1[C@H]1OCCC1)NS(=O)(=O)[C@@H](C)[C@H](C)C1=NC=C(C=N1)C BPYZHXRJLIJAOG-BXWFABGCSA-N 0.000 claims description 4
- 125000002015 acyclic group Chemical group 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000005879 dioxolanyl group Chemical group 0.000 claims description 4
- 125000002757 morpholinyl group Chemical group 0.000 claims description 4
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 4
- 229940124530 sulfonamide Drugs 0.000 claims description 4
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 claims description 4
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 claims description 4
- GSXUHLGBQGDOQU-KGLIPLIRSA-N (2R)-N-[4-(2,6-dimethoxyphenyl)-5-[(3R)-oxolan-3-yl]-1,2,4-triazol-3-yl]-1-(5-fluoropyrimidin-2-yl)propane-2-sulfonamide Chemical compound COC1=C(C(=CC=C1)OC)N1C(=NN=C1[C@@H]1COCC1)NS(=O)(=O)[C@@H](CC1=NC=C(C=N1)F)C GSXUHLGBQGDOQU-KGLIPLIRSA-N 0.000 claims description 3
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- YNCQIEXEMALWCD-AUUYWEPGSA-N (1R)-1-(3-chlorophenyl)-N-[4-(2,6-dimethoxyphenyl)-5-[(2R)-oxolan-2-yl]-1,2,4-triazol-3-yl]ethanesulfonamide Chemical compound ClC=1C=C(C=CC=1)[C@@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@@H]1OCCC1 YNCQIEXEMALWCD-AUUYWEPGSA-N 0.000 claims description 2
- YNCQIEXEMALWCD-KUHUBIRLSA-N (1R)-1-(3-chlorophenyl)-N-[4-(2,6-dimethoxyphenyl)-5-[(2S)-oxolan-2-yl]-1,2,4-triazol-3-yl]ethanesulfonamide Chemical compound ClC=1C=C(C=CC=1)[C@@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@H]1OCCC1 YNCQIEXEMALWCD-KUHUBIRLSA-N 0.000 claims description 2
- OXTKDCQJNUYZLM-AUUYWEPGSA-N (1R)-N-[4-(2,6-dimethoxyphenyl)-5-[(2R)-oxolan-2-yl]-1,2,4-triazol-3-yl]-1-(2-fluorophenyl)ethanesulfonamide Chemical compound COC1=C(C(=CC=C1)OC)N1C(=NN=C1[C@@H]1OCCC1)NS(=O)(=O)[C@H](C)C1=C(C=CC=C1)F OXTKDCQJNUYZLM-AUUYWEPGSA-N 0.000 claims description 2
- BCSGLWRTLZJPJJ-FOIQADDNSA-N (1R)-N-[4-(2,6-dimethoxyphenyl)-5-[(2R)-oxolan-2-yl]-1,2,4-triazol-3-yl]-1-(3-methoxyphenyl)ethanesulfonamide Chemical compound COC1=C(C(=CC=C1)OC)N1C(=NN=C1[C@@H]1OCCC1)NS(=O)(=O)[C@H](C)C1=CC(=CC=C1)OC BCSGLWRTLZJPJJ-FOIQADDNSA-N 0.000 claims description 2
- IKZOCWWAIULGTN-DNVCBOLYSA-N (1R)-N-[4-(2,6-dimethoxyphenyl)-5-[(2R)-oxolan-2-yl]-1,2,4-triazol-3-yl]-1-phenylethanesulfonamide Chemical compound COC1=C(C(=CC=C1)OC)N1C(=NN=C1[C@@H]1OCCC1)NS(=O)(=O)[C@H](C)C1=CC=CC=C1 IKZOCWWAIULGTN-DNVCBOLYSA-N 0.000 claims description 2
- OXTKDCQJNUYZLM-KUHUBIRLSA-N (1R)-N-[4-(2,6-dimethoxyphenyl)-5-[(2S)-oxolan-2-yl]-1,2,4-triazol-3-yl]-1-(2-fluorophenyl)ethanesulfonamide Chemical compound COC1=C(C(=CC=C1)OC)N1C(=NN=C1[C@H]1OCCC1)NS(=O)(=O)[C@H](C)C1=C(C=CC=C1)F OXTKDCQJNUYZLM-KUHUBIRLSA-N 0.000 claims description 2
- BCSGLWRTLZJPJJ-QRWLVFNGSA-N (1R)-N-[4-(2,6-dimethoxyphenyl)-5-[(2S)-oxolan-2-yl]-1,2,4-triazol-3-yl]-1-(3-methoxyphenyl)ethanesulfonamide Chemical compound COC1=C(C(=CC=C1)OC)N1C(=NN=C1[C@H]1OCCC1)NS(=O)(=O)[C@H](C)C1=CC(=CC=C1)OC BCSGLWRTLZJPJJ-QRWLVFNGSA-N 0.000 claims description 2
- IKZOCWWAIULGTN-BEFAXECRSA-N (1R)-N-[4-(2,6-dimethoxyphenyl)-5-[(2S)-oxolan-2-yl]-1,2,4-triazol-3-yl]-1-phenylethanesulfonamide Chemical compound COC1=C(C(=CC=C1)OC)N1C(=NN=C1[C@H]1OCCC1)NS(=O)(=O)[C@H](C)C1=CC=CC=C1 IKZOCWWAIULGTN-BEFAXECRSA-N 0.000 claims description 2
- RNZRZYNPPZDOKL-KPCPBYSCSA-N (1R,2R)-N-[4-(2,6-dimethoxyphenyl)-5-[(2S)-1,4-dioxan-2-yl]-1,2,4-triazol-3-yl]-1-imidazo[1,2-a]pyridin-2-yl-1-propan-2-yloxypropane-2-sulfonamide Chemical compound COC1=C(C(=CC=C1)OC)N1C(=NN=C1[C@@H]1OCCOC1)NS(=O)(=O)[C@@H]([C@H](OC(C)C)C=1N=C2N(C=CC=C2)C=1)C RNZRZYNPPZDOKL-KPCPBYSCSA-N 0.000 claims description 2
- BUZXEXTUZXIYMF-CFGMGRTJSA-N (1R,2S)-1-(5-chloropyridin-2-yl)-N-[4-(1,3-dimethoxypropan-2-yl)-5-[(2R,5R)-5-methyloxolan-2-yl]-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=CC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C(COC)COC)[C@@H]1O[C@@H](CC1)C)OC BUZXEXTUZXIYMF-CFGMGRTJSA-N 0.000 claims description 2
- BUZXEXTUZXIYMF-LSOMNZGLSA-N (1R,2S)-1-(5-chloropyridin-2-yl)-N-[4-(1,3-dimethoxypropan-2-yl)-5-[(2S,5S)-5-methyloxolan-2-yl]-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=CC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C(COC)COC)[C@H]1O[C@H](CC1)C)OC BUZXEXTUZXIYMF-LSOMNZGLSA-N 0.000 claims description 2
- IBUVIMGETBMIAT-JBYOLUDKSA-N (1R,2S)-1-(5-chloropyridin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(2R)-1,4-dioxan-2-yl]-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=CC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@H]1OCCOC1)OC IBUVIMGETBMIAT-JBYOLUDKSA-N 0.000 claims description 2
- IBUVIMGETBMIAT-ZKYUUJBMSA-N (1R,2S)-1-(5-chloropyridin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(2S)-1,4-dioxan-2-yl]-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=CC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@@H]1OCCOC1)OC IBUVIMGETBMIAT-ZKYUUJBMSA-N 0.000 claims description 2
- OJGKPRBCMROPIG-HUBLWGQQSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxy-N-[4-(1,2-oxazol-3-ylmethyl)-5-[(3R)-oxolan-3-yl]-1,2,4-triazol-3-yl]propane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1CC1=NOC=C1)[C@@H]1COCC1)OC OJGKPRBCMROPIG-HUBLWGQQSA-N 0.000 claims description 2
- OJGKPRBCMROPIG-ZOWXZIJZSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxy-N-[4-(1,2-oxazol-3-ylmethyl)-5-[(3S)-oxolan-3-yl]-1,2,4-triazol-3-yl]propane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1CC1=NOC=C1)[C@H]1COCC1)OC OJGKPRBCMROPIG-ZOWXZIJZSA-N 0.000 claims description 2
- MGEAXSVXDGIFNC-CFVMTHIKSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxy-N-[4-(1-methylcyclopropyl)-5-[(2R)-oxan-2-yl]-1,2,4-triazol-3-yl]propane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1(CC1)C)[C@@H]1OCCCC1)OC MGEAXSVXDGIFNC-CFVMTHIKSA-N 0.000 claims description 2
- DAMKKGRQUZLJPD-YUTCNCBUSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxy-N-[4-(1-methylcyclopropyl)-5-[(2R)-oxolan-2-yl]-1,2,4-triazol-3-yl]propane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1(CC1)C)[C@@H]1OCCC1)OC DAMKKGRQUZLJPD-YUTCNCBUSA-N 0.000 claims description 2
- ARNRZJBJDGPFBC-OSRDXIQISA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxy-N-[4-(1-methylcyclopropyl)-5-[(2R,5R)-5-methyloxolan-2-yl]-1,2,4-triazol-3-yl]propane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1(CC1)C)[C@@H]1O[C@@H](CC1)C)OC ARNRZJBJDGPFBC-OSRDXIQISA-N 0.000 claims description 2
- MGEAXSVXDGIFNC-QEJZJMRPSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxy-N-[4-(1-methylcyclopropyl)-5-[(2S)-oxan-2-yl]-1,2,4-triazol-3-yl]propane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1(CC1)C)[C@H]1OCCCC1)OC MGEAXSVXDGIFNC-QEJZJMRPSA-N 0.000 claims description 2
- DAMKKGRQUZLJPD-UBHSHLNASA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxy-N-[4-(1-methylcyclopropyl)-5-[(2S)-oxolan-2-yl]-1,2,4-triazol-3-yl]propane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1(CC1)C)[C@H]1OCCC1)OC DAMKKGRQUZLJPD-UBHSHLNASA-N 0.000 claims description 2
- ARNRZJBJDGPFBC-JURCDPSOSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxy-N-[4-(1-methylcyclopropyl)-5-[(2S,5S)-5-methyloxolan-2-yl]-1,2,4-triazol-3-yl]propane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1(CC1)C)[C@H]1O[C@H](CC1)C)OC ARNRZJBJDGPFBC-JURCDPSOSA-N 0.000 claims description 2
- OMDWQYFOXCVDQV-YDHLFZDLSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxy-N-[4-(1-methylcyclopropyl)-5-[(3R)-oxan-3-yl]-1,2,4-triazol-3-yl]propane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1(CC1)C)[C@@H]1COCCC1)OC OMDWQYFOXCVDQV-YDHLFZDLSA-N 0.000 claims description 2
- KEMZCROSOGUJDK-OBJOEFQTSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxy-N-[4-(1-methylcyclopropyl)-5-[(3R)-oxolan-3-yl]-1,2,4-triazol-3-yl]propane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1(CC1)C)[C@@H]1COCC1)OC KEMZCROSOGUJDK-OBJOEFQTSA-N 0.000 claims description 2
- OMDWQYFOXCVDQV-GUTXKFCHSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxy-N-[4-(1-methylcyclopropyl)-5-[(3S)-oxan-3-yl]-1,2,4-triazol-3-yl]propane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1(CC1)C)[C@H]1COCCC1)OC OMDWQYFOXCVDQV-GUTXKFCHSA-N 0.000 claims description 2
- KEMZCROSOGUJDK-SCRDCRAPSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxy-N-[4-(1-methylcyclopropyl)-5-[(3S)-oxolan-3-yl]-1,2,4-triazol-3-yl]propane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1(CC1)C)[C@H]1COCC1)OC KEMZCROSOGUJDK-SCRDCRAPSA-N 0.000 claims description 2
- UJAPPLJAOXSWNZ-OBJOEFQTSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxy-N-[4-(2-methoxyethyl)-5-[(3R)-oxolan-3-yl]-1,2,4-triazol-3-yl]propane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1CCOC)[C@@H]1COCC1)OC UJAPPLJAOXSWNZ-OBJOEFQTSA-N 0.000 claims description 2
- UJAPPLJAOXSWNZ-SCRDCRAPSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxy-N-[4-(2-methoxyethyl)-5-[(3S)-oxolan-3-yl]-1,2,4-triazol-3-yl]propane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1CCOC)[C@H]1COCC1)OC UJAPPLJAOXSWNZ-SCRDCRAPSA-N 0.000 claims description 2
- OIHYWUQDIRVTRY-KKXDTOCCSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxy-N-[4-(2-methoxyphenyl)-5-[(2S)-oxolan-2-yl]-1,2,4-triazol-3-yl]propane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1)OC)[C@H]1OCCC1)OC OIHYWUQDIRVTRY-KKXDTOCCSA-N 0.000 claims description 2
- COFGCIUSDJZIMU-WBAXXEDZSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxy-N-[4-(2-methylphenyl)-5-[(2S)-oxolan-2-yl]-1,2,4-triazol-3-yl]propane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1)C)[C@H]1OCCC1)OC COFGCIUSDJZIMU-WBAXXEDZSA-N 0.000 claims description 2
- MOVJKKHMOUDOBO-CLWVCHIJSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxy-N-[4-[1-(methoxymethyl)cyclopropyl]-5-[(2R,5R)-5-methyloxolan-2-yl]-1,2,4-triazol-3-yl]propane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1(CC1)COC)[C@@H]1O[C@@H](CC1)C)OC MOVJKKHMOUDOBO-CLWVCHIJSA-N 0.000 claims description 2
- MOVJKKHMOUDOBO-SDADXPQNSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxy-N-[4-[1-(methoxymethyl)cyclopropyl]-5-[(2S,5S)-5-methyloxolan-2-yl]-1,2,4-triazol-3-yl]propane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1(CC1)COC)[C@H]1O[C@H](CC1)C)OC MOVJKKHMOUDOBO-SDADXPQNSA-N 0.000 claims description 2
- AJZGPKAPHJHEIG-YDHLFZDLSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxy-N-[4-[1-(methoxymethyl)cyclopropyl]-5-[(3R)-oxolan-3-yl]-1,2,4-triazol-3-yl]propane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1(CC1)COC)[C@@H]1COCC1)OC AJZGPKAPHJHEIG-YDHLFZDLSA-N 0.000 claims description 2
- AJZGPKAPHJHEIG-GUTXKFCHSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxy-N-[4-[1-(methoxymethyl)cyclopropyl]-5-[(3S)-oxolan-3-yl]-1,2,4-triazol-3-yl]propane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1(CC1)COC)[C@H]1COCC1)OC AJZGPKAPHJHEIG-GUTXKFCHSA-N 0.000 claims description 2
- NDWDSAYXTDVKHW-KOZAUXTDSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxy-N-[5-[(2R,5R)-5-methyloxolan-2-yl]-4-(1,2-oxazol-3-ylmethyl)-1,2,4-triazol-3-yl]propane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1CC1=NOC=C1)[C@@H]1O[C@@H](CC1)C)OC NDWDSAYXTDVKHW-KOZAUXTDSA-N 0.000 claims description 2
- XTYVLCWMTYXVJZ-GFOFROLCSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxy-N-[5-[(2R,5R)-5-methyloxolan-2-yl]-4-(oxan-4-yl)-1,2,4-triazol-3-yl]propane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1CCOCC1)[C@@H]1O[C@@H](CC1)C)OC XTYVLCWMTYXVJZ-GFOFROLCSA-N 0.000 claims description 2
- NDWDSAYXTDVKHW-APYUEPQZSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxy-N-[5-[(2S,5S)-5-methyloxolan-2-yl]-4-(1,2-oxazol-3-ylmethyl)-1,2,4-triazol-3-yl]propane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1CC1=NOC=C1)[C@H]1O[C@H](CC1)C)OC NDWDSAYXTDVKHW-APYUEPQZSA-N 0.000 claims description 2
- XTYVLCWMTYXVJZ-PYTWLRIVSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxy-N-[5-[(2S,5S)-5-methyloxolan-2-yl]-4-(oxan-4-yl)-1,2,4-triazol-3-yl]propane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1CCOCC1)[C@H]1O[C@H](CC1)C)OC XTYVLCWMTYXVJZ-PYTWLRIVSA-N 0.000 claims description 2
- RFTNZOMLEGBFHE-OBJOEFQTSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxy-N-[5-[(3R)-oxolan-3-yl]-4-propan-2-yl-1,2,4-triazol-3-yl]propane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C(C)C)[C@@H]1COCC1)OC RFTNZOMLEGBFHE-OBJOEFQTSA-N 0.000 claims description 2
- RFTNZOMLEGBFHE-SCRDCRAPSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxy-N-[5-[(3S)-oxolan-3-yl]-4-propan-2-yl-1,2,4-triazol-3-yl]propane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C(C)C)[C@H]1COCC1)OC RFTNZOMLEGBFHE-SCRDCRAPSA-N 0.000 claims description 2
- JHOITNDGSWGNSR-RCBQFDQVSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-[4-(1,3-dimethoxypropan-2-yl)-5-[(2R)-1,4-dioxan-2-yl]-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C(COC)COC)[C@H]1OCCOC1)OC JHOITNDGSWGNSR-RCBQFDQVSA-N 0.000 claims description 2
- PIBNOZWTXLWVHX-XKQJLSEDSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-[4-(1,3-dimethoxypropan-2-yl)-5-[(2R)-5,5-dimethyloxolan-2-yl]-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C(COC)COC)[C@@H]1OC(CC1)(C)C)OC PIBNOZWTXLWVHX-XKQJLSEDSA-N 0.000 claims description 2
- CDXHVFNZMRIAJQ-MAZHCROVSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-[4-(1,3-dimethoxypropan-2-yl)-5-[(2R)-oxolan-2-yl]-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C(COC)COC)[C@@H]1OCCC1)OC CDXHVFNZMRIAJQ-MAZHCROVSA-N 0.000 claims description 2
- STIVEMBSMQLOSU-GFOFROLCSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-[4-(1,3-dimethoxypropan-2-yl)-5-[(2R,5R)-5-methyloxolan-2-yl]-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C(COC)COC)[C@@H]1O[C@@H](CC1)C)OC STIVEMBSMQLOSU-GFOFROLCSA-N 0.000 claims description 2
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- PIBNOZWTXLWVHX-JQFCIGGWSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-[4-(1,3-dimethoxypropan-2-yl)-5-[(2S)-5,5-dimethyloxolan-2-yl]-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C(COC)COC)[C@H]1OC(CC1)(C)C)OC PIBNOZWTXLWVHX-JQFCIGGWSA-N 0.000 claims description 2
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- QEXKWTJAGOCDGM-XZOAIXRZSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-[4-(dicyclopropylmethyl)-5-[(2S)-1,4-dioxan-2-yl]-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C(C1CC1)C1CC1)[C@@H]1OCCOC1)OC QEXKWTJAGOCDGM-XZOAIXRZSA-N 0.000 claims description 2
- RYPCMCRKCZLNRK-UBHSHLNASA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-[5-[(2R)-1,4-dioxan-2-yl]-4-(1-methylcyclopropyl)-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1(CC1)C)[C@H]1OCCOC1)OC RYPCMCRKCZLNRK-UBHSHLNASA-N 0.000 claims description 2
- FDRDIZUMQHTOEY-WBAXXEDZSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-[5-[(2R)-1,4-dioxan-2-yl]-4-(1-pyridin-3-ylcyclopropyl)-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1(CC1)C=1C=NC=CC=1)[C@H]1OCCOC1)OC FDRDIZUMQHTOEY-WBAXXEDZSA-N 0.000 claims description 2
- WLSUJWIETQKAJZ-UBHSHLNASA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-[5-[(2R)-1,4-dioxan-2-yl]-4-(2-methoxyethyl)-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1CCOC)[C@H]1OCCOC1)OC WLSUJWIETQKAJZ-UBHSHLNASA-N 0.000 claims description 2
- JCUPILQTSQNWCJ-RCBQFDQVSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-[5-[(2R)-1,4-dioxan-2-yl]-4-(oxan-4-yl)-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1CCOCC1)[C@H]1OCCOC1)OC JCUPILQTSQNWCJ-RCBQFDQVSA-N 0.000 claims description 2
- QCLYUESLHHOBRT-QEJZJMRPSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-[5-[(2R)-1,4-dioxan-2-yl]-4-[1-(methoxymethyl)cyclopropyl]-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1(CC1)COC)[C@H]1OCCOC1)OC QCLYUESLHHOBRT-QEJZJMRPSA-N 0.000 claims description 2
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- OFBHHBVPGMKKSA-UBHSHLNASA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-[5-[(2R)-1,4-dioxan-2-yl]-4-propan-2-yl-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C(C)C)[C@H]1OCCOC1)OC OFBHHBVPGMKKSA-UBHSHLNASA-N 0.000 claims description 2
- ZIBZYNHHYPWJMU-CFVMTHIKSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-[5-[(2R)-5,5-dimethyloxolan-2-yl]-4-(2-methoxyethyl)-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1CCOC)[C@@H]1OC(CC1)(C)C)OC ZIBZYNHHYPWJMU-CFVMTHIKSA-N 0.000 claims description 2
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- JREYMZBQEWALNV-IMJJTQAJSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-[5-[(2R)-5,5-dimethyloxolan-2-yl]-4-[1-(methoxymethyl)cyclopropyl]-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1(CC1)COC)[C@@H]1OC(CC1)(C)C)OC JREYMZBQEWALNV-IMJJTQAJSA-N 0.000 claims description 2
- KONPUAFBYOBCTD-CFVMTHIKSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-[5-[(2R)-5,5-dimethyloxolan-2-yl]-4-propan-2-yl-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C(C)C)[C@@H]1OC(CC1)(C)C)OC KONPUAFBYOBCTD-CFVMTHIKSA-N 0.000 claims description 2
- RYPCMCRKCZLNRK-YUTCNCBUSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-[5-[(2S)-1,4-dioxan-2-yl]-4-(1-methylcyclopropyl)-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1(CC1)C)[C@@H]1OCCOC1)OC RYPCMCRKCZLNRK-YUTCNCBUSA-N 0.000 claims description 2
- FDRDIZUMQHTOEY-QGTPRVQTSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-[5-[(2S)-1,4-dioxan-2-yl]-4-(1-pyridin-3-ylcyclopropyl)-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1(CC1)C=1C=NC=CC=1)[C@@H]1OCCOC1)OC FDRDIZUMQHTOEY-QGTPRVQTSA-N 0.000 claims description 2
- WLSUJWIETQKAJZ-YUTCNCBUSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-[5-[(2S)-1,4-dioxan-2-yl]-4-(2-methoxyethyl)-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1CCOC)[C@@H]1OCCOC1)OC WLSUJWIETQKAJZ-YUTCNCBUSA-N 0.000 claims description 2
- JCUPILQTSQNWCJ-MAZHCROVSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-[5-[(2S)-1,4-dioxan-2-yl]-4-(oxan-4-yl)-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1CCOCC1)[C@@H]1OCCOC1)OC JCUPILQTSQNWCJ-MAZHCROVSA-N 0.000 claims description 2
- QCLYUESLHHOBRT-CFVMTHIKSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-[5-[(2S)-1,4-dioxan-2-yl]-4-[1-(methoxymethyl)cyclopropyl]-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1(CC1)COC)[C@@H]1OCCOC1)OC QCLYUESLHHOBRT-CFVMTHIKSA-N 0.000 claims description 2
- PZUHMWUVQHWWCB-MAZHCROVSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-[5-[(2S)-1,4-dioxan-2-yl]-4-pentan-3-yl-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C(CC)CC)[C@@H]1OCCOC1)OC PZUHMWUVQHWWCB-MAZHCROVSA-N 0.000 claims description 2
- OFBHHBVPGMKKSA-YUTCNCBUSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-[5-[(2S)-1,4-dioxan-2-yl]-4-propan-2-yl-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C(C)C)[C@@H]1OCCOC1)OC OFBHHBVPGMKKSA-YUTCNCBUSA-N 0.000 claims description 2
- ZIBZYNHHYPWJMU-QEJZJMRPSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-[5-[(2S)-5,5-dimethyloxolan-2-yl]-4-(2-methoxyethyl)-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1CCOC)[C@H]1OC(CC1)(C)C)OC ZIBZYNHHYPWJMU-QEJZJMRPSA-N 0.000 claims description 2
- QYAAHOLIPLWKRC-JQFCIGGWSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-[5-[(2S)-5,5-dimethyloxolan-2-yl]-4-(oxan-4-yl)-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1CCOCC1)[C@H]1OC(CC1)(C)C)OC QYAAHOLIPLWKRC-JQFCIGGWSA-N 0.000 claims description 2
- JREYMZBQEWALNV-BPUTZDHNSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-[5-[(2S)-5,5-dimethyloxolan-2-yl]-4-[1-(methoxymethyl)cyclopropyl]-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1(CC1)COC)[C@H]1OC(CC1)(C)C)OC JREYMZBQEWALNV-BPUTZDHNSA-N 0.000 claims description 2
- KONPUAFBYOBCTD-QEJZJMRPSA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-[5-[(2S)-5,5-dimethyloxolan-2-yl]-4-propan-2-yl-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C(C)C)[C@H]1OC(CC1)(C)C)OC KONPUAFBYOBCTD-QEJZJMRPSA-N 0.000 claims description 2
- LLTQTXIUBQSURO-GNOCETLISA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-[5-[(3R)-2,3-dihydro-1,4-benzodioxin-3-yl]-4-(2,6-dimethoxyphenyl)-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@@H]1COC2=C(O1)C=CC=C2)OC LLTQTXIUBQSURO-GNOCETLISA-N 0.000 claims description 2
- LLTQTXIUBQSURO-XFEAKLGESA-N (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-[5-[(3S)-2,3-dihydro-1,4-benzodioxin-3-yl]-4-(2,6-dimethoxyphenyl)-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@H]1COC2=C(O1)C=CC=C2)OC LLTQTXIUBQSURO-XFEAKLGESA-N 0.000 claims description 2
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- QFAIFUMCODOBJA-AHMDFLBRSA-N (1R,2S)-N-[4-(1,3-dimethoxypropan-2-yl)-5-[(2R,5R)-5-methyloxolan-2-yl]-1,2,4-triazol-3-yl]-1-methoxy-1-(5-methoxypyrazin-2-yl)propane-2-sulfonamide Chemical compound COCC(COC)N1C(=NN=C1[C@@H]1O[C@@H](CC1)C)NS(=O)(=O)[C@H]([C@@H](C1=NC=C(N=C1)OC)OC)C QFAIFUMCODOBJA-AHMDFLBRSA-N 0.000 claims description 2
- QFAIFUMCODOBJA-IPQUUHLSSA-N (1R,2S)-N-[4-(1,3-dimethoxypropan-2-yl)-5-[(2S,5S)-5-methyloxolan-2-yl]-1,2,4-triazol-3-yl]-1-methoxy-1-(5-methoxypyrazin-2-yl)propane-2-sulfonamide Chemical compound COCC(COC)N1C(=NN=C1[C@H]1O[C@H](CC1)C)NS(=O)(=O)[C@H]([C@@H](C1=NC=C(N=C1)OC)OC)C QFAIFUMCODOBJA-IPQUUHLSSA-N 0.000 claims description 2
- QIUHOIHDIHSWIA-WBAXXEDZSA-N (1R,2S)-N-[4-(1-cyclopropylcyclopropyl)-5-[(2R)-1,4-dioxan-2-yl]-1,2,4-triazol-3-yl]-1-methoxy-1-(5-methylpyrazin-2-yl)propane-2-sulfonamide Chemical compound C1(CC1)(C1CC1)N1C(=NN=C1[C@H]1OCCOC1)NS(=O)(=O)[C@H]([C@@H](C1=NC=C(N=C1)C)OC)C QIUHOIHDIHSWIA-WBAXXEDZSA-N 0.000 claims description 2
- QIUHOIHDIHSWIA-QGTPRVQTSA-N (1R,2S)-N-[4-(1-cyclopropylcyclopropyl)-5-[(2S)-1,4-dioxan-2-yl]-1,2,4-triazol-3-yl]-1-methoxy-1-(5-methylpyrazin-2-yl)propane-2-sulfonamide Chemical compound C1(CC1)(C1CC1)N1C(=NN=C1[C@@H]1OCCOC1)NS(=O)(=O)[C@H]([C@@H](C1=NC=C(N=C1)C)OC)C QIUHOIHDIHSWIA-QGTPRVQTSA-N 0.000 claims description 2
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- XPYLGESKHMGSFK-YROCYRMSSA-N (1R,2S)-N-[4-(2,6-dimethoxyphenyl)-5-[(1S)-3-oxo-1,2-dihydroisoindol-1-yl]-1,2,4-triazol-3-yl]-1-methoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide Chemical compound COC1=C(C(=CC=C1)OC)N1C(=NN=C1[C@H]1NC(C2=CC=CC=C12)=O)NS(=O)(=O)[C@H]([C@@H](C1=NC=C(C=N1)C)OC)C XPYLGESKHMGSFK-YROCYRMSSA-N 0.000 claims description 2
- JPLJRDHCJNCHJP-LRQRDZAKSA-N (1R,2S)-N-[4-(2,6-dimethoxyphenyl)-5-[(2R)-1,4-dioxan-2-yl]-1,2,4-triazol-3-yl]-1-ethoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide Chemical compound COC1=C(C(=CC=C1)OC)N1C(=NN=C1[C@H]1OCCOC1)NS(=O)(=O)[C@H]([C@@H](C1=NC=C(C=N1)C)OCC)C JPLJRDHCJNCHJP-LRQRDZAKSA-N 0.000 claims description 2
- KPCXWMKGOOHRER-QSFXBCCZSA-N (1R,2S)-N-[4-(2,6-dimethoxyphenyl)-5-[(2R)-1,4-dioxan-2-yl]-1,2,4-triazol-3-yl]-1-methoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide Chemical compound COC1=C(C(=CC=C1)OC)N1C(=NN=C1[C@H]1OCCOC1)NS(=O)(=O)[C@H]([C@@H](C1=NC=C(C=N1)C)OC)C KPCXWMKGOOHRER-QSFXBCCZSA-N 0.000 claims description 2
- JPLJRDHCJNCHJP-SCWSEQNSSA-N (1R,2S)-N-[4-(2,6-dimethoxyphenyl)-5-[(2S)-1,4-dioxan-2-yl]-1,2,4-triazol-3-yl]-1-ethoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide Chemical compound COC1=C(C(=CC=C1)OC)N1C(=NN=C1[C@@H]1OCCOC1)NS(=O)(=O)[C@H]([C@@H](C1=NC=C(C=N1)C)OCC)C JPLJRDHCJNCHJP-SCWSEQNSSA-N 0.000 claims description 2
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- CUDHZIYHVTVXSU-YQVWRLOYSA-N (1S,2S)-N-[4-(4,6-dimethoxypyrimidin-5-yl)-5-[(3S)-5,5-dimethyloxolan-3-yl]-1,2,4-triazol-3-yl]-1-(5-methylpyrimidin-2-yl)-1-propan-2-yloxypropane-2-sulfonamide Chemical compound COC1=NC=NC(=C1N1C(=NN=C1[C@H]1COC(C1)(C)C)NS(=O)(=O)[C@H]([C@@H](OC(C)C)C1=NC=C(C=N1)C)C)OC CUDHZIYHVTVXSU-YQVWRLOYSA-N 0.000 claims description 2
- UXOOAXUGAVPRKF-JJRVBVJISA-N (1S,2S)-N-[4-(4,6-dimethoxypyrimidin-5-yl)-5-[(3S)-oxolan-3-yl]-1,2,4-triazol-3-yl]-1-(5-fluoropyrimidin-2-yl)-1-propan-2-yloxypropane-2-sulfonamide Chemical compound COC1=NC=NC(=C1N1C(=NN=C1[C@H]1COCC1)NS(=O)(=O)[C@H]([C@@H](OC(C)C)C1=NC=C(C=N1)F)C)OC UXOOAXUGAVPRKF-JJRVBVJISA-N 0.000 claims description 2
- YHFUVVSKXUSBDY-SQGPQFPESA-N (1S,2S)-N-[4-(4,6-dimethoxypyrimidin-5-yl)-5-[(3S)-oxolan-3-yl]-1,2,4-triazol-3-yl]-1-(5-methylpyridin-2-yl)-1-propan-2-yloxypropane-2-sulfonamide Chemical compound COC1=NC=NC(=C1N1C(=NN=C1[C@H]1COCC1)NS(=O)(=O)[C@H]([C@@H](OC(C)C)C1=NC=C(C=C1)C)C)OC YHFUVVSKXUSBDY-SQGPQFPESA-N 0.000 claims description 2
- ZUDPSDJCMSHQIU-HRQSHJORSA-N (1S,2S)-N-[5-[(2R,5R)-5-methyloxolan-2-yl]-4-(oxan-4-yl)-1,2,4-triazol-3-yl]-1-(5-methylpyrazin-2-yl)-1-propan-2-yloxypropane-2-sulfonamide Chemical compound CC(C)O[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1CCOCC1)[C@@H]1O[C@@H](CC1)C)C1=NC=C(N=C1)C ZUDPSDJCMSHQIU-HRQSHJORSA-N 0.000 claims description 2
- ZUDPSDJCMSHQIU-IDPBPBMLSA-N (1S,2S)-N-[5-[(2S,5S)-5-methyloxolan-2-yl]-4-(oxan-4-yl)-1,2,4-triazol-3-yl]-1-(5-methylpyrazin-2-yl)-1-propan-2-yloxypropane-2-sulfonamide Chemical compound CC(C)O[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1CCOCC1)[C@H]1O[C@H](CC1)C)C1=NC=C(N=C1)C ZUDPSDJCMSHQIU-IDPBPBMLSA-N 0.000 claims description 2
- NDCQDRDLTJDDHP-CQSZACIVSA-N (2R)-N-[4-(2,6-dimethoxyphenyl)-5-(oxan-4-yl)-1,2,4-triazol-3-yl]-1-(5-fluoropyrimidin-2-yl)propane-2-sulfonamide Chemical compound COC1=C(C(=CC=C1)OC)N1C(=NN=C1C1CCOCC1)NS(=O)(=O)[C@@H](CC1=NC=C(C=N1)F)C NDCQDRDLTJDDHP-CQSZACIVSA-N 0.000 claims description 2
- BPYZHXRJLIJAOG-GPMSIDNRSA-N (2R,3S)-N-[4-(2,6-dimethoxyphenyl)-5-[(2R)-oxolan-2-yl]-1,2,4-triazol-3-yl]-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide Chemical compound COC1=C(C(=CC=C1)OC)N1C(=NN=C1[C@@H]1OCCC1)NS(=O)(=O)[C@H](C)[C@@H](C)C1=NC=C(C=N1)C BPYZHXRJLIJAOG-GPMSIDNRSA-N 0.000 claims description 2
- BPYZHXRJLIJAOG-MDZRGWNJSA-N (2R,3S)-N-[4-(2,6-dimethoxyphenyl)-5-[(2S)-oxolan-2-yl]-1,2,4-triazol-3-yl]-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide Chemical compound COC1=C(C(=CC=C1)OC)N1C(=NN=C1[C@H]1OCCC1)NS(=O)(=O)[C@H](C)[C@@H](C)C1=NC=C(C=N1)C BPYZHXRJLIJAOG-MDZRGWNJSA-N 0.000 claims description 2
- NDCQDRDLTJDDHP-AWEZNQCLSA-N (2S)-N-[4-(2,6-dimethoxyphenyl)-5-(oxan-4-yl)-1,2,4-triazol-3-yl]-1-(5-fluoropyrimidin-2-yl)propane-2-sulfonamide Chemical compound COC1=C(C(=CC=C1)OC)N1C(=NN=C1C1CCOCC1)NS(=O)(=O)[C@H](CC1=NC=C(C=N1)F)C NDCQDRDLTJDDHP-AWEZNQCLSA-N 0.000 claims description 2
- DIWOWOARXDSCSY-MMMWYMCRSA-N (2S,3R)-3-(5-chloropyridin-2-yl)-N-[4-(1,3-dimethoxypropan-2-yl)-5-[(2R,5R)-5-methyloxolan-2-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=CC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C(COC)COC)[C@@H]1O[C@@H](CC1)C)C DIWOWOARXDSCSY-MMMWYMCRSA-N 0.000 claims description 2
- DIWOWOARXDSCSY-XLPNERPQSA-N (2S,3R)-3-(5-chloropyridin-2-yl)-N-[4-(1,3-dimethoxypropan-2-yl)-5-[(2S,5S)-5-methyloxolan-2-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=CC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C(COC)COC)[C@H]1O[C@H](CC1)C)C DIWOWOARXDSCSY-XLPNERPQSA-N 0.000 claims description 2
- WIESRPAQTCSRBT-AVYPCKFXSA-N (2S,3R)-3-(5-chloropyridin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(2R)-1,4-dioxan-2-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=CC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@H]1OCCOC1)C WIESRPAQTCSRBT-AVYPCKFXSA-N 0.000 claims description 2
- WIESRPAQTCSRBT-AUSJPIAWSA-N (2S,3R)-3-(5-chloropyridin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(2S)-1,4-dioxan-2-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=CC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@@H]1OCCOC1)C WIESRPAQTCSRBT-AUSJPIAWSA-N 0.000 claims description 2
- WGMBZBMSCUCBOQ-JYJNAYRXSA-N (2S,3R)-3-(5-chloropyridin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(3R)-oxolan-3-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=CC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@@H]1COCC1)C WGMBZBMSCUCBOQ-JYJNAYRXSA-N 0.000 claims description 2
- WGMBZBMSCUCBOQ-HRCADAONSA-N (2S,3R)-3-(5-chloropyridin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(3S)-oxolan-3-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=CC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@H]1COCC1)C WGMBZBMSCUCBOQ-HRCADAONSA-N 0.000 claims description 2
- VORIAAHTVHYHSH-IHRRRGAJSA-N (2S,3R)-3-(5-chloropyridin-2-yl)-N-[4-(4,6-dimethoxypyrimidin-5-yl)-5-[(3R)-oxolan-3-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=CC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C=1C(=NC=NC=1OC)OC)[C@@H]1COCC1)C VORIAAHTVHYHSH-IHRRRGAJSA-N 0.000 claims description 2
- VORIAAHTVHYHSH-MELADBBJSA-N (2S,3R)-3-(5-chloropyridin-2-yl)-N-[4-(4,6-dimethoxypyrimidin-5-yl)-5-[(3S)-oxolan-3-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=CC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C=1C(=NC=NC=1OC)OC)[C@H]1COCC1)C VORIAAHTVHYHSH-MELADBBJSA-N 0.000 claims description 2
- OZOCBLMBZORRAJ-XJIUQZFPSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(1,3-dimethoxypropan-2-yl)-5-[(2R,5R)-5-methyloxolan-2-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C(COC)COC)[C@@H]1O[C@@H](CC1)C)C OZOCBLMBZORRAJ-XJIUQZFPSA-N 0.000 claims description 2
- OZOCBLMBZORRAJ-WSMBLCCSSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(1,3-dimethoxypropan-2-yl)-5-[(2S,5S)-5-methyloxolan-2-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C(COC)COC)[C@H]1O[C@H](CC1)C)C OZOCBLMBZORRAJ-WSMBLCCSSA-N 0.000 claims description 2
- KZBYMAIFHGGDEA-STQMWFEESA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-(oxetan-3-yl)-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)C1COC1)C KZBYMAIFHGGDEA-STQMWFEESA-N 0.000 claims description 2
- GMYWUQDDAWGEKV-VFCRVFHLSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(1R)-3-oxo-1,2-dihydroisoindol-1-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@@H]1NC(C2=CC=CC=C12)=O)C GMYWUQDDAWGEKV-VFCRVFHLSA-N 0.000 claims description 2
- GMYWUQDDAWGEKV-GXZWQRSESA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(1S)-3-oxo-1,2-dihydroisoindol-1-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@H]1NC(C2=CC=CC=C12)=O)C GMYWUQDDAWGEKV-GXZWQRSESA-N 0.000 claims description 2
- DFCFNMKNWZCPGI-KCQAQPDRSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(2R)-5-oxopyrrolidin-2-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@@H]1NC(CC1)=O)C DFCFNMKNWZCPGI-KCQAQPDRSA-N 0.000 claims description 2
- QIBDMBGERPDXOG-GDZNZVCISA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(2R)-oxetan-2-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@@H]1OCC1)C QIBDMBGERPDXOG-GDZNZVCISA-N 0.000 claims description 2
- QPZRZYJXSTYOHW-SUNYJGFJSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(2R)-oxolan-2-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@@H]1OCCC1)C QPZRZYJXSTYOHW-SUNYJGFJSA-N 0.000 claims description 2
- UJDVFVCIAZZKBX-IVSAIRAKSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(2R,3R)-2-methyloxolan-3-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@@H]1[C@H](OCC1)C)C UJDVFVCIAZZKBX-IVSAIRAKSA-N 0.000 claims description 2
- UJDVFVCIAZZKBX-QSJFSLAZSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(2R,3S)-2-methyloxolan-3-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@H]1[C@H](OCC1)C)C UJDVFVCIAZZKBX-QSJFSLAZSA-N 0.000 claims description 2
- CFHOOOBIMCPINC-VPCSNGCSSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(2R,3S)-3-methyloxolan-2-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@@H]1OCC[C@@H]1C)C CFHOOOBIMCPINC-VPCSNGCSSA-N 0.000 claims description 2
- QJGFMFVAPBLUFD-DZKIICNBSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(2S)-1-methyl-5-oxopyrrolidin-2-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@H]1N(C(CC1)=O)C)C QJGFMFVAPBLUFD-DZKIICNBSA-N 0.000 claims description 2
- DFCFNMKNWZCPGI-YDHLFZDLSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(2S)-5-oxopyrrolidin-2-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@H]1NC(CC1)=O)C DFCFNMKNWZCPGI-YDHLFZDLSA-N 0.000 claims description 2
- NLQSTGPCPQZARL-DOXZYTNZSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(2S)-oxan-2-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@H]1OCCCC1)C NLQSTGPCPQZARL-DOXZYTNZSA-N 0.000 claims description 2
- QPZRZYJXSTYOHW-DEYYWGMASA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(2S)-oxolan-2-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@H]1OCCC1)C QPZRZYJXSTYOHW-DEYYWGMASA-N 0.000 claims description 2
- UJDVFVCIAZZKBX-JKQORVJESA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(2S,3R)-2-methyloxolan-3-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@@H]1[C@@H](OCC1)C)C UJDVFVCIAZZKBX-JKQORVJESA-N 0.000 claims description 2
- CFHOOOBIMCPINC-XGKMFUNXSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(2S,3R)-3-methyloxolan-2-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@H]1OCC[C@H]1C)C CFHOOOBIMCPINC-XGKMFUNXSA-N 0.000 claims description 2
- UJDVFVCIAZZKBX-QBYUYEEZSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(2S,3S)-2-methyloxolan-3-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@H]1[C@@H](OCC1)C)C UJDVFVCIAZZKBX-QBYUYEEZSA-N 0.000 claims description 2
- ATEYZZIPCFWFHJ-KKUMJFAQSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(3R)-1,1-dioxothiolan-3-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@@H]1CS(CC1)(=O)=O)C ATEYZZIPCFWFHJ-KKUMJFAQSA-N 0.000 claims description 2
- QBEZGOKGDFEBRG-JYJNAYRXSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(3R)-5,5-dimethyloxolan-3-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@@H]1COC(C1)(C)C)C QBEZGOKGDFEBRG-JYJNAYRXSA-N 0.000 claims description 2
- YWDFZMLAPFPKOC-JYJNAYRXSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(3R)-oxan-3-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@@H]1COCCC1)C YWDFZMLAPFPKOC-JYJNAYRXSA-N 0.000 claims description 2
- PZPKWNCTGJSYPV-UGUYLWEFSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(3R,5R)-5-methyloxolan-3-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@@H]1CO[C@@H](C1)C)C PZPKWNCTGJSYPV-UGUYLWEFSA-N 0.000 claims description 2
- PZPKWNCTGJSYPV-VGWMRTNUSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(3R,5S)-5-methyloxolan-3-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@@H]1CO[C@H](C1)C)C PZPKWNCTGJSYPV-VGWMRTNUSA-N 0.000 claims description 2
- ATEYZZIPCFWFHJ-SOUVJXGZSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(3S)-1,1-dioxothiolan-3-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@H]1CS(CC1)(=O)=O)C ATEYZZIPCFWFHJ-SOUVJXGZSA-N 0.000 claims description 2
- QBEZGOKGDFEBRG-HRCADAONSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(3S)-5,5-dimethyloxolan-3-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@H]1COC(C1)(C)C)C QBEZGOKGDFEBRG-HRCADAONSA-N 0.000 claims description 2
- YWDFZMLAPFPKOC-HRCADAONSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(3S)-oxan-3-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@H]1COCCC1)C YWDFZMLAPFPKOC-HRCADAONSA-N 0.000 claims description 2
- PZPKWNCTGJSYPV-FXUDXRNXSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(3S,5R)-5-methyloxolan-3-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@H]1CO[C@@H](C1)C)C PZPKWNCTGJSYPV-FXUDXRNXSA-N 0.000 claims description 2
- PZPKWNCTGJSYPV-YHUYYLMFSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(3S,5S)-5-methyloxolan-3-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@H]1CO[C@H](C1)C)C PZPKWNCTGJSYPV-YHUYYLMFSA-N 0.000 claims description 2
- NCGSQPNCMZFWSW-AVGNSLFASA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(3,5-dibromo-2,6-dimethoxyphenyl)-5-[(3R)-oxolan-3-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C(=CC(=C1OC)Br)Br)OC)[C@@H]1COCC1)C NCGSQPNCMZFWSW-AVGNSLFASA-N 0.000 claims description 2
- NCGSQPNCMZFWSW-RWMBFGLXSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(3,5-dibromo-2,6-dimethoxyphenyl)-5-[(3S)-oxolan-3-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C(=CC(=C1OC)Br)Br)OC)[C@H]1COCC1)C NCGSQPNCMZFWSW-RWMBFGLXSA-N 0.000 claims description 2
- JRSSWEAHIWVNDI-QWRGUYRKSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(4,6-dimethoxypyrimidin-5-yl)-5-(oxetan-3-yl)-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C=1C(=NC=NC=1OC)OC)C1COC1)C JRSSWEAHIWVNDI-QWRGUYRKSA-N 0.000 claims description 2
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- WVIFDQROZSJUBZ-SGMGOOAPSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(4,6-dimethoxypyrimidin-5-yl)-5-[(2R)-oxolan-2-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C=1C(=NC=NC=1OC)OC)[C@@H]1OCCC1)C WVIFDQROZSJUBZ-SGMGOOAPSA-N 0.000 claims description 2
- BHXHWRLOLDPEFO-YDHLFZDLSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(4,6-dimethoxypyrimidin-5-yl)-5-[(2S)-oxan-2-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C=1C(=NC=NC=1OC)OC)[C@H]1OCCCC1)C BHXHWRLOLDPEFO-YDHLFZDLSA-N 0.000 claims description 2
- WVIFDQROZSJUBZ-OBJOEFQTSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(4,6-dimethoxypyrimidin-5-yl)-5-[(2S)-oxolan-2-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C=1C(=NC=NC=1OC)OC)[C@H]1OCCC1)C WVIFDQROZSJUBZ-OBJOEFQTSA-N 0.000 claims description 2
- QSPKTLRKKHRLDP-IHRRRGAJSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(4,6-dimethoxypyrimidin-5-yl)-5-[(3R)-5,5-dimethyloxolan-3-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C=1C(=NC=NC=1OC)OC)[C@@H]1COC(C1)(C)C)C QSPKTLRKKHRLDP-IHRRRGAJSA-N 0.000 claims description 2
- NUBGVIVXTNUSQX-IHRRRGAJSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(4,6-dimethoxypyrimidin-5-yl)-5-[(3R)-oxan-3-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C=1C(=NC=NC=1OC)OC)[C@@H]1COCCC1)C NUBGVIVXTNUSQX-IHRRRGAJSA-N 0.000 claims description 2
- RDVAGJCMFVSKDY-AVGNSLFASA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(4,6-dimethoxypyrimidin-5-yl)-5-[(3R)-oxolan-3-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C=1C(=NC=NC=1OC)OC)[C@@H]1COCC1)C RDVAGJCMFVSKDY-AVGNSLFASA-N 0.000 claims description 2
- QSPKTLRKKHRLDP-MELADBBJSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(4,6-dimethoxypyrimidin-5-yl)-5-[(3S)-5,5-dimethyloxolan-3-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C=1C(=NC=NC=1OC)OC)[C@H]1COC(C1)(C)C)C QSPKTLRKKHRLDP-MELADBBJSA-N 0.000 claims description 2
- NUBGVIVXTNUSQX-MELADBBJSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(4,6-dimethoxypyrimidin-5-yl)-5-[(3S)-oxan-3-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C=1C(=NC=NC=1OC)OC)[C@H]1COCCC1)C NUBGVIVXTNUSQX-MELADBBJSA-N 0.000 claims description 2
- RDVAGJCMFVSKDY-RWMBFGLXSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-(4,6-dimethoxypyrimidin-5-yl)-5-[(3S)-oxolan-3-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C=1C(=NC=NC=1OC)OC)[C@H]1COCC1)C RDVAGJCMFVSKDY-RWMBFGLXSA-N 0.000 claims description 2
- FGVAZGKVSTWMBX-RFQIPJPRSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-[(1R)-1-(1,2-oxazol-3-yl)ethyl]-5-[(3S)-oxolan-3-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1[C@H](C)C1=NOC=C1)[C@H]1COCC1)C FGVAZGKVSTWMBX-RFQIPJPRSA-N 0.000 claims description 2
- FGVAZGKVSTWMBX-XDQVBPFNSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[4-[(1S)-1-(1,2-oxazol-3-yl)ethyl]-5-[(3S)-oxolan-3-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1[C@@H](C)C1=NOC=C1)[C@H]1COCC1)C FGVAZGKVSTWMBX-XDQVBPFNSA-N 0.000 claims description 2
- VUXICSLTXWKKPX-XEZPLFJOSA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[5-[(2R)-1,4-dioxan-2-yl]-4-(oxan-4-yl)-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1CCOCC1)[C@H]1OCCOC1)C VUXICSLTXWKKPX-XEZPLFJOSA-N 0.000 claims description 2
- VUXICSLTXWKKPX-HEHGZKQESA-N (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-[5-[(2S)-1,4-dioxan-2-yl]-4-(oxan-4-yl)-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound ClC=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1CCOCC1)[C@@H]1OCCOC1)C VUXICSLTXWKKPX-HEHGZKQESA-N 0.000 claims description 2
- SPSOEYPITQZQNO-DZKIICNBSA-N (2S,3R)-3-(5-cyanopyridin-2-yl)-N-[4-(4,6-dimethoxypyrimidin-5-yl)-5-[(3R)-oxolan-3-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound C(#N)C=1C=CC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C=1C(=NC=NC=1OC)OC)[C@@H]1COCC1)C SPSOEYPITQZQNO-DZKIICNBSA-N 0.000 claims description 2
- SPSOEYPITQZQNO-OFQRWUPVSA-N (2S,3R)-3-(5-cyanopyridin-2-yl)-N-[4-(4,6-dimethoxypyrimidin-5-yl)-5-[(3S)-oxolan-3-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound C(#N)C=1C=CC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C=1C(=NC=NC=1OC)OC)[C@H]1COCC1)C SPSOEYPITQZQNO-OFQRWUPVSA-N 0.000 claims description 2
- YYBMAGUIWUSERO-YZVOILCLSA-N (2S,3R)-3-(5-cyanopyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(2R)-oxolan-2-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound C(#N)C=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@@H]1OCCC1)C YYBMAGUIWUSERO-YZVOILCLSA-N 0.000 claims description 2
- YYBMAGUIWUSERO-DOXZYTNZSA-N (2S,3R)-3-(5-cyanopyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(2S)-oxolan-2-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound C(#N)C=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@H]1OCCC1)C YYBMAGUIWUSERO-DOXZYTNZSA-N 0.000 claims description 2
- LHHNMTPUSKEJAF-ZOBUZTSGSA-N (2S,3R)-3-(5-cyanopyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(3R)-oxolan-3-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound C(#N)C=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@@H]1COCC1)C LHHNMTPUSKEJAF-ZOBUZTSGSA-N 0.000 claims description 2
- LHHNMTPUSKEJAF-YQQAZPJKSA-N (2S,3R)-3-(5-cyanopyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(3S)-oxolan-3-yl]-1,2,4-triazol-3-yl]butane-2-sulfonamide Chemical compound C(#N)C=1C=NC(=NC=1)[C@H]([C@H](C)S(=O)(=O)NC1=NN=C(N1C1=C(C=CC=C1OC)OC)[C@H]1COCC1)C LHHNMTPUSKEJAF-YQQAZPJKSA-N 0.000 claims description 2
- UDRPPLVMLPUTNS-XJIUQZFPSA-N (2S,3R)-N-[4-(1,3-dimethoxypropan-2-yl)-5-[(2R,5R)-5-methyloxolan-2-yl]-1,2,4-triazol-3-yl]-3-(5-fluoropyrimidin-2-yl)butane-2-sulfonamide Chemical compound COCC(COC)N1C(=NN=C1[C@@H]1O[C@@H](CC1)C)NS(=O)(=O)[C@@H](C)[C@H](C)C1=NC=C(C=N1)F UDRPPLVMLPUTNS-XJIUQZFPSA-N 0.000 claims description 2
- OKZVPYQUYFGWNZ-LDDOYCOJSA-N (2S,3R)-N-[4-(1,3-dimethoxypropan-2-yl)-5-[(2R,5R)-5-methyloxolan-2-yl]-1,2,4-triazol-3-yl]-3-(5-methoxypyrazin-2-yl)butane-2-sulfonamide Chemical compound COCC(COC)N1C(=NN=C1[C@@H]1O[C@@H](CC1)C)NS(=O)(=O)[C@@H](C)[C@H](C)C1=NC=C(N=C1)OC OKZVPYQUYFGWNZ-LDDOYCOJSA-N 0.000 claims description 2
- OWGRJMRNJKNQAK-LDDOYCOJSA-N (2S,3R)-N-[4-(1,3-dimethoxypropan-2-yl)-5-[(2R,5R)-5-methyloxolan-2-yl]-1,2,4-triazol-3-yl]-3-(5-methoxypyrimidin-2-yl)butane-2-sulfonamide Chemical compound COCC(COC)N1C(=NN=C1[C@@H]1O[C@@H](CC1)C)NS(=O)(=O)[C@@H](C)[C@H](C)C1=NC=C(C=N1)OC OWGRJMRNJKNQAK-LDDOYCOJSA-N 0.000 claims description 2
- UDRPPLVMLPUTNS-WSMBLCCSSA-N (2S,3R)-N-[4-(1,3-dimethoxypropan-2-yl)-5-[(2S,5S)-5-methyloxolan-2-yl]-1,2,4-triazol-3-yl]-3-(5-fluoropyrimidin-2-yl)butane-2-sulfonamide Chemical compound COCC(COC)N1C(=NN=C1[C@H]1O[C@H](CC1)C)NS(=O)(=O)[C@@H](C)[C@H](C)C1=NC=C(C=N1)F UDRPPLVMLPUTNS-WSMBLCCSSA-N 0.000 claims description 2
- OKZVPYQUYFGWNZ-XSWJXKHESA-N (2S,3R)-N-[4-(1,3-dimethoxypropan-2-yl)-5-[(2S,5S)-5-methyloxolan-2-yl]-1,2,4-triazol-3-yl]-3-(5-methoxypyrazin-2-yl)butane-2-sulfonamide Chemical compound COCC(COC)N1C(=NN=C1[C@H]1O[C@H](CC1)C)NS(=O)(=O)[C@@H](C)[C@H](C)C1=NC=C(N=C1)OC OKZVPYQUYFGWNZ-XSWJXKHESA-N 0.000 claims description 2
- OWGRJMRNJKNQAK-XSWJXKHESA-N (2S,3R)-N-[4-(1,3-dimethoxypropan-2-yl)-5-[(2S,5S)-5-methyloxolan-2-yl]-1,2,4-triazol-3-yl]-3-(5-methoxypyrimidin-2-yl)butane-2-sulfonamide Chemical compound COCC(COC)N1C(=NN=C1[C@H]1O[C@H](CC1)C)NS(=O)(=O)[C@@H](C)[C@H](C)C1=NC=C(C=N1)OC OWGRJMRNJKNQAK-XSWJXKHESA-N 0.000 claims description 2
- DODGIMOEWGLMRR-GRDNDAEWSA-N (2S,3R)-N-[4-(2,6-difluorophenyl)-5-[(2R)-oxolan-2-yl]-1,2,4-triazol-3-yl]-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide Chemical compound FC1=C(C(=CC=C1)F)N1C(=NN=C1[C@@H]1OCCC1)NS(=O)(=O)[C@@H](C)[C@H](C)C1=NC=C(C=N1)C DODGIMOEWGLMRR-GRDNDAEWSA-N 0.000 claims description 2
- DODGIMOEWGLMRR-ZQIUZPCESA-N (2S,3R)-N-[4-(2,6-difluorophenyl)-5-[(2S)-oxolan-2-yl]-1,2,4-triazol-3-yl]-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide Chemical compound FC1=C(C(=CC=C1)F)N1C(=NN=C1[C@H]1OCCC1)NS(=O)(=O)[C@@H](C)[C@H](C)C1=NC=C(C=N1)C DODGIMOEWGLMRR-ZQIUZPCESA-N 0.000 claims description 2
- RQOBXESUTNRCQA-JYJNAYRXSA-N (2S,3R)-N-[4-(2,6-difluorophenyl)-5-[(3R)-oxan-3-yl]-1,2,4-triazol-3-yl]-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide Chemical compound FC1=C(C(=CC=C1)F)N1C(=NN=C1[C@@H]1COCCC1)NS(=O)(=O)[C@@H](C)[C@H](C)C1=NC=C(C=N1)C RQOBXESUTNRCQA-JYJNAYRXSA-N 0.000 claims description 2
- MKAIPVPLSGRNQT-KKUMJFAQSA-N (2S,3R)-N-[4-(2,6-difluorophenyl)-5-[(3R)-oxolan-3-yl]-1,2,4-triazol-3-yl]-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide Chemical compound FC1=C(C(=CC=C1)F)N1C(=NN=C1[C@@H]1COCC1)NS(=O)(=O)[C@@H](C)[C@H](C)C1=NC=C(C=N1)C MKAIPVPLSGRNQT-KKUMJFAQSA-N 0.000 claims description 2
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- AMAXYHCDGOXFOP-UXGZOIFOSA-N (2S,3R)-N-[4-[2,6-bis(trideuteriomethoxy)phenyl]-5-[(3R)-oxolan-3-yl]-1,2,4-triazol-3-yl]-3-(5-chloropyrimidin-2-yl)butane-2-sulfonamide Chemical compound [2H]C(OC1=C(C(=CC=C1)OC([2H])([2H])[2H])N1C(=NN=C1[C@@H]1COCC1)NS(=O)(=O)[C@@H](C)[C@H](C)C1=NC=C(C=N1)Cl)([2H])[2H] AMAXYHCDGOXFOP-UXGZOIFOSA-N 0.000 claims description 2
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- KRIVMUNAXONHMO-VWNVYAMZSA-N (2S,3R)-N-[5-[(3S,8aR)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-yl]-4-(2,6-dimethoxyphenyl)-1,2,4-triazol-3-yl]-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide Chemical compound COC1=C(C(=CC=C1)OC)N1C(=NN=C1[C@@H]1CN2[C@@H](CO1)CCC2)NS(=O)(=O)[C@@H](C)[C@H](C)C1=NC=C(C=N1)C KRIVMUNAXONHMO-VWNVYAMZSA-N 0.000 claims description 2
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- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- HBCQSNAFLVXVAY-UHFFFAOYSA-N pyrimidine-2-thiol Chemical compound SC1=NC=CC=N1 HBCQSNAFLVXVAY-UHFFFAOYSA-N 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 229960001455 quinapril Drugs 0.000 description 1
- JSDRRTOADPPCHY-HSQYWUDLSA-N quinapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2=CC=CC=C2C1)C(O)=O)CC1=CC=CC=C1 JSDRRTOADPPCHY-HSQYWUDLSA-N 0.000 description 1
- 229960001007 quinaprilat Drugs 0.000 description 1
- FLSLEGPOVLMJMN-YSSFQJQWSA-N quinaprilat Chemical compound C([C@H](N[C@@H](C)C(=O)N1[C@@H](CC2=CC=CC=C2C1)C(O)=O)C(O)=O)CC1=CC=CC=C1 FLSLEGPOVLMJMN-YSSFQJQWSA-N 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical compound C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 description 1
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- HDACQVRGBOVJII-JBDAPHQKSA-N ramipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 HDACQVRGBOVJII-JBDAPHQKSA-N 0.000 description 1
- 229960002231 ramiprilat Drugs 0.000 description 1
- KEDYTOTWMPBSLG-HILJTLORSA-N ramiprilat Chemical compound C([C@H](N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)C(O)=O)CC1=CC=CC=C1 KEDYTOTWMPBSLG-HILJTLORSA-N 0.000 description 1
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- 238000004007 reversed phase HPLC Methods 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229950007981 sacubitrilat Drugs 0.000 description 1
- 230000000894 saliuretic effect Effects 0.000 description 1
- 210000002235 sarcomere Anatomy 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
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- 238000004904 shortening Methods 0.000 description 1
- VFWRGKJLLYDFBY-UHFFFAOYSA-N silver;hydrate Chemical compound O.[Ag].[Ag] VFWRGKJLLYDFBY-UHFFFAOYSA-N 0.000 description 1
- PHWXUGHIIBDVKD-UHFFFAOYSA-N sitaxentan Chemical compound CC1=NOC(NS(=O)(=O)C2=C(SC=C2)C(=O)CC=2C(=CC=3OCOC=3C=2)C)=C1Cl PHWXUGHIIBDVKD-UHFFFAOYSA-N 0.000 description 1
- 229960002578 sitaxentan Drugs 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000002594 sorbent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- BUUPQKDIAURBJP-UHFFFAOYSA-N sulfinic acid Chemical compound OS=O BUUPQKDIAURBJP-UHFFFAOYSA-N 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229960002613 tamsulosin Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960000651 tasosartan Drugs 0.000 description 1
- ADXGNEYLLLSOAR-UHFFFAOYSA-N tasosartan Chemical compound C12=NC(C)=NC(C)=C2CCC(=O)N1CC(C=C1)=CC=C1C1=CC=CC=C1C=1N=NNN=1 ADXGNEYLLLSOAR-UHFFFAOYSA-N 0.000 description 1
- 229960005187 telmisartan Drugs 0.000 description 1
- 229960004084 temocapril Drugs 0.000 description 1
- FIQOFIRCTOWDOW-BJLQDIEVSA-N temocapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N(CC(O)=O)C[C@H](SC1)C=1SC=CC=1)=O)CC1=CC=CC=C1 FIQOFIRCTOWDOW-BJLQDIEVSA-N 0.000 description 1
- 229960001693 terazosin Drugs 0.000 description 1
- VCKUSRYTPJJLNI-UHFFFAOYSA-N terazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1CCCO1 VCKUSRYTPJJLNI-UHFFFAOYSA-N 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229950000584 tezosentan Drugs 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 229940083085 thiazide derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 1
- 229950003137 tiapamil Drugs 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000009529 traumatic brain injury Effects 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- AHZJKOKFZJYCLG-UHFFFAOYSA-K trifluoromethanesulfonate;ytterbium(3+) Chemical compound [Yb+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F AHZJKOKFZJYCLG-UHFFFAOYSA-K 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 229960004699 valsartan Drugs 0.000 description 1
- ACWBQPMHZXGDFX-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=NN1 ACWBQPMHZXGDFX-QFIPXVFZSA-N 0.000 description 1
- 229940051537 valsartan and sacubitril Drugs 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 206010047302 ventricular tachycardia Diseases 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- CITILBVTAYEWKR-UHFFFAOYSA-L zinc trifluoromethanesulfonate Substances [Zn+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F CITILBVTAYEWKR-UHFFFAOYSA-L 0.000 description 1
- ZMLPZCGHASSGEA-UHFFFAOYSA-M zinc trifluoromethanesulfonate Chemical compound [Zn+2].[O-]S(=O)(=O)C(F)(F)F ZMLPZCGHASSGEA-UHFFFAOYSA-M 0.000 description 1
- 229960002769 zofenopril Drugs 0.000 description 1
- IAIDUHCBNLFXEF-MNEFBYGVSA-N zofenopril Chemical compound C([C@@H](C)C(=O)N1[C@@H](C[C@@H](C1)SC=1C=CC=CC=1)C(O)=O)SC(=O)C1=CC=CC=C1 IAIDUHCBNLFXEF-MNEFBYGVSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
Definitions
- the present invention relates to compounds capable of acting as agonists of the APJ Receptor, and compositions that include compounds that are agonists of the APJ Receptor.
- the compounds and compositions may be used to activate the APJ Receptor and to treat various disease conditions.
- An example of one area where such compounds may be used is in the treatment of cardiovascular conditions.
- the compounds may be used to improve contractility and ejection fraction in subjects with chronic heart failure and may be used to treat patients with heart failure with reduced ejection fraction and patients with heart failure with preserved ejection fraction.
- Apelin is the endogenous ligand for APJ (APLNR, angiotensin receptor like-1).
- APLNR angiotensin receptor like-1
- the APJ receptor is a member of the rhodopsin-like G protein-coupled receptor (GPCR) family.
- GPCR G protein-coupled receptor
- the apelin/APJ system has been observed in many tissues such as heart, kidney, pancreas, lung and the central nervous system. This suggests diverse roles of the system in the physiology and pathology of mammals.
- Apelin peptides are processed from a 77 residue pre-pro form into smaller bioactive fragments, mainly a 36 residue form (Apelin 42-77- also referred to as Apelin-36) and a smaller 13 residue polypeptide (Apelin 65-77-also referred to as Apelin- 13) Hosoya et al., J. Biol. Chem.275:21061-21067, 2000.
- Apelin peptides were previously determined to be endogenous ligands for the orphan APJ receptor, a member of the seven transmembrane G-protein-coupled receptor superfamily. Tatemoto et al., Biochem. Biophysi. Res.
- exogenous apelin increases contractility at subnanomolar concentrations in atrial strips and whole rat hearts, and increases sarcomere shortening by up to 140% in isolated cardiomyocyctes.
- Apelin also has a potent inotropic effect in an ex vivo isolated heart assay.
- acute apelin infusion restores ejection fraction, increases cardiac output and reduces left ventricular end-diastolic pressure in rats with chronic heart failure.
- Exogenous apelin potently enhances myocardial contractility without inducing left ventricular hypertrophy concomitant with reduction in ventricular preload and afterload.
- a shortened 12 amino acid-apelin peptide having ligand activity on APJ was reported in a 2009 patent (U.S. Pat. No.7,635,751).
- the peptide could have a substitution of one non-canonical amino acid.
- WO 2013/111110 A2 and U.S. Pat. No.8,673,848, cyclic mimetics of apelin have also been reported.
- PCT/US2013/075773 describes a group of modifications, including substitution of non-canonical amino acids and changes at the N- and C-terminal of the apelin molecule that can affect, inter alia, the potency of the molecule.
- the increased potency can be a result of increased half-life or decreased degradation relative to wild- type apelin.
- WO 2014/044738 discloses various benzimidazole- carboxylic acid amide derivatives as modulators of the APJ Receptor.
- Other small molecule agonists of the APJ receptor are disclosed in U.S. Pat. Appl. Pub. No. US 2016/0340336 and WO 2016/187308.
- Still other small molecule agonists of the APJ receptor are disclosed in WO 2015/184011 and in WO 2015/188073.
- the present application discloses such agonists of the APJ receptor s that may be suitable for use as therapeutic agents in treating a variety of conditions. These compounds may find particular benefit in treating cardiovascular conditions. For example, such compounds may be beneficial in treating conditions such as chronic systolic heart failure and chronic diastolic heart failure.
- the invention provides a compound of Formula I or Formula II:
- R 1 is a 3-, 4-, 5-, 6-, 7-, or 8-membered saturated or partially saturated heterocyclic group that includes 1, 2, or 3 heteroatoms independently selected from N, O, or S that is unsubstituted or is substituted with 1, 2, or 3 R 1a substituents;
- R 1a in each instance is independently selected from -F, -Cl, -Br, -I, -C 1 -C 6 alkyl, - C 1 -C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -CN, -OH, -O-(C 1 - C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -C 2 -C 6 alkenyl, -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl)-OH, -O-(C 1 -C 6 haloalkyl
- R 1a’ is in each instance independently selected from -F, -Cl, -Br, -I, -C 1 -C 6 alkyl, - C 1 -C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, C 3 -C 8 cycloalkyl -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), - CN, -OH, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -C 2 -C 6 alkenyl, -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl)- OH, -
- R 2 is selected from -H, or C 1 -C 4 alkyl or is absent in the compounds of Formula II;
- R 3 is selected from an unsubstituted C 1 -C 10 alkyl, a C 1 -C 10 alkyl substituted with 1, 2, or 3 R 3a substituents, a group of formula -(CR 3b R 3c )-Q, a group of formula
- R 3a in each instance is independently selected from -F, -Cl, -CN, -OH, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -NH 2 , -NH(C 1 -C 6 alkyl), or–N(C 1 - C 6 alkyl) 2 ;
- R 3b and R 3c are independently selected from–H, -F, -Cl, -CN, -C 1 -C 6 alkyl, -C 1 - C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, -OH, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or–N(C 1 -C 6 alkyl) 2 ;
- R 3d and R 3e are independently selected from–H, -F, -Cl, -CN, -C 1 -C 6 alkyl, -C 1 - C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, -OH, -(C 1 -C 6 alkyl)-OH, -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl)-phenyl, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O- (C 1 -C 6 perhaloalkyl), -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -NH 2 , -
- R 3f and R 3g are independently selected from–H, -F, -Cl, -CN, -C 1 -C 6 alkyl, -C 1 - C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, -OH, -(C 1 -C 6 alkyl)-OH, -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -O-(C 2 -C 6 alkenyl), -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or–N(
- Q is a monocyclic or bicyclic C 6 -C 10 aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a C 3 -C 8 cycloalkyl group, a 3 to 10 membered heterocyclyl group containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, wherein the C 6 -C 10 aryl, the heteroaryl, the cycloalkyl, and the heterocyclyl Q groups are unsubstituted or are substituted with 1, 2, 3, or 4 R Q substituents; and further wherein the Q heterocyclyl group may additionally be substituted with 1 or 2 oxo substituents, and the Q heteroaryl group may include an N-oxide if the heteroaryl includes a N heteroatom;
- R 4 is selected from a monocyclic or bicyclic C 6 -C 10 aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a monocyclic or bicyclic heterocyclyl group with 5 to 10 ring members containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S, or a monocyclic 3-6 membered cycloalkyl group, wherein the C 6 -C 10 aryl, the heteroaryl, the heterocyclyl, and the cycloalkyl R 4 group are unsubstituted or are substituted with 1, 2, 3, or 4 R 4a substituents; and
- the invention provides a compound of Formula I or Formula II:
- R 1 is a 3-, 4-, 5-, 6-, 7-, or 8-membered saturated or partially saturated heterocyclic group that includes 1, 2, or 3 heteroatoms independently selected from N, O, or S that is unsubstituted or is substituted with 1, 2, or 3 R 1a substituents;
- R 1a in each instance is independently selected from -F, -Cl, -Br, -I, -C 1 -C 6 alkyl, - C 1 -C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -CN, -OH, -O-(C 1 - C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -C 2 -C 6 alkenyl, -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl)-OH, -O-(C 1 -C 6 haloalkyl
- R 2 is selected from -H, or C 1 -C 4 alkyl or is absent in the compounds of Formula II;
- R 3 is selected from an unsubstituted C 1 -C 10 alkyl, a C 1 -C 10 alkyl substituted with 1, 2, or 3 R 3a substituents, a group of formula -(CR 3b R 3c )-Q, a group of formula
- R 3a in each instance is independently selected from -F, -Cl, -CN, -OH, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -NH 2 , -NH(C 1 -C 6 alkyl), or–N(C 1 - C 6 alkyl) 2 ;
- R 3b and R 3c are independently selected from–H, -F, -Cl, -CN, -C 1 -C 6 alkyl, -C 1 - C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, -OH, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or–N(C 1 -C 6 alkyl) 2 ;
- R 3d and R 3e are independently selected from–H, -F, -Cl, -CN, -C 1 -C 6 alkyl, -C 1 - C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, -OH, -(C 1 -C 6 alkyl)-OH, -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl)-phenyl, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O- (C 1 -C 6 perhaloalkyl), -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -NH 2 , -
- Q is a monocyclic or bicyclic C 6 -C 10 aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a C 3 -C 8 cycloalkyl group, a 3 to 10 membered heterocyclyl group containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, wherein the C 6 -C 10 aryl, the heteroaryl, the cycloalkyl, and the heterocyclyl Q groups are unsubstituted or are substituted with 1, 2, 3, or 4 R Q substituents; and further wherein the Q heterocyclyl group may additionally be substituted with 1 or 2 oxo substituents, and the Q heteroaryl group may include an N-oxide if the heteroaryl includes a N heteroatom;
- R 4 is selected from a monocyclic or bicyclic C 6 -C 10 aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a monocyclic or bicyclic heterocyclyl group with 5 to 10 ring members containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S, a monocyclic 3-6 membered cycloalkyl group, or a straight or branched chain C 1 - C 6 alkyl group, wherein the C 6 -C 10 aryl, the heteroaryl, and the heterocyclyl R 4 group are unsubstituted or are substituted with 1, 2, 3, or 4 R 4a substituents, and further wherein the cycloalkyl R 4 group is unsubstituted or is substituted with 1, 2, 3, or 4 R 4b substituents, and further wherein the straight or branched chain C 1 -C 6 alkyl R 4
- compositions that include at least one pharmaceutically acceptable excipient, carrier or diluent and the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments.
- the invention provides a method of treating a cardiovascular condition.
- Such methods typically include administering to a subject an effective amount of the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments or a pharmaceutical composition of any of the embodiments.
- the cardiovascular condition is heart failure.
- the cardiovascular condition is heart failure with reduced ejection fraction whereas in other embodiments it is heart failure with preserved ejection fraction.
- the cardiovascular condition is chronic systolic heart failure or chronic diastolic heart failure.
- the cardiovascular condition is acute heart failure whereas in other embodiments, the cardiovascular condition is hypertension.
- the invention provides a method of improving cardiac contractility in a subject.
- Such methods typically include administering to the subject an effective amount of the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments or a pharmaceutical composition of any of the embodiments.
- the invention provides a method of increasing ejection fraction in a subject suffering from a cardiovascular condition.
- Such methods typically include administering to the subject an effective amount of the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments or a pharmaceutical composition of any of the embodiments.
- the ejection fraction is increased in the subject after administration.
- the invention provides a method of treating a condition in a subject where it is desired to activate the APJ Receptor.
- Such methods typically include administering to the subject an effective amount of the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments or a pharmaceutical composition of any of the embodiments.
- the condition is obesity or diabetes whereas in other such embodiments, the condition is diabetic nephropathy or chronic kidney disease.
- the invention provides the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments or a pharmaceutical composition of any of the embodiments for use in treating a cardiovascular condition.
- the cardiovascular condition is heart failure.
- the cardiovascular condition is heart failure with reduced ejection fraction whereas in other embodiments it is heart failure with preserved ejection fraction.
- the cardiovascular condition is chronic systolic heart failure or chronic diastolic heart failure.
- the cardiovascular condition is acute heart failure whereas in other embodiments, the cardiovascular condition is hypertension.
- the invention provides the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments or a pharmaceutical composition of any of the embodiments for improving the cardiac contractility in a subject suffering from a cardiovascular condition.
- the invention provides the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments or a pharmaceutical composition of any of the embodiments for improving the ejection fraction in a subject suffering from a cardiovascular condition.
- the invention provides the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments or a pharmaceutical composition of any of the embodiments for treating a condition in a subject where it is desired to activate the APJ Receptor.
- the condition is obesity or diabetes whereas in other such embodiments, the condition is diabetic nephropathy or chronic kidney disease.
- FIG.1A is a graph of left ventricular dP/dt max as a function of concentration of Example 49.0 compared with vehicle in ex vivo naive Sprague Dawley rat hearts obtained using the Langendorff apparatus. This shows Example 49.0 increases load independent cardiac contractility in isolated perfused rat hearts.
- FIG.1B is a graph of left ventricular dP/dt min as a function of concentration of Example 49.0 compared with vehicle in ex vivo naive Sprague Dawley rat hearts obtained using the Langendorff apparatus. This shows Example 49.0 increases load independent cardiac relaxation in isolated perfused rat hearts.
- FIG.2A is a graph of left ventricular dP/dt max as a function of concentration of Example 60.0 compared with vehicle in ex vivo naive Sprague Dawley rat hearts obtained using the Langendorff apparatus. This shows Example 60.0 increases load independent cardiac contractility in isolated perfused rat hearts.
- FIG.2B is a graph of left ventricular dP/dt min as a function of concentration of Example 60.0 compared with vehicle in ex vivo naive Sprague Dawley rat hearts obtained using the Langendorff apparatus. This shows Example 60.0 increases load independent cardiac relaxation in isolated perfused rat hearts.
- FIG.3 is a graph plotting different concentrations of angiotensin (AngII) with fixed concentration of pyr apelin-13 added to the human APJ-AT1R (angiotensin Type 1) double stable CHO cell line.
- IP1 inositol phosphate accumulation
- TR-FRET Time-resolved fluorescence resonance energy
- FIG.4 is a graph plotting different concentrations of angiotensin (AngII) with fixed concentration of pyr apelin-13 added to the human APJ receptor expressed in the CHO cell line.
- IP1 inositol phosphate accumulation
- TR-FRET Time-resolved fluorescence resonance energy
- FIG.5 is a graph plotting different concentrations of angiotensin (AngII) with fixed concentration of pyr apelin-13 added to the human AT1R receptor expressed in the CHO cell line.
- IP1 inositol phosphate accumulation
- TR-FRET Time-resolved fluorescence resonance energy
- any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence. If the chemical structure and chemical name conflict, the chemical structure is determinative of the identity of the compound.
- the compounds of the present disclosure may contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers or diastereomers.
- any chemical structures within the scope of the specification depicted, in whole or in part, with a relative configuration encompass all possible enantiomers and stereoisomers of the illustrated compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures.
- Enantiomeric and stereoisomeric mixtures can be resolved into the component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan.
- composition is meant to be open ended, i.e., all encompassing and non-limiting. It may be used herein synonymously with“having” or“including”. Comprising is intended to include each and every indicated or recited component or element(s) while not excluding any other components or elements. For example, if a composition is said to comprise A and B. This means that the composition has A and B in it, but may also include C or even C, D, E, and other additional components.
- Certain compounds of the invention may possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, enantiomers, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the invention.
- atropisomers and mixtures thereof such as those resulting from restricted rotation about two aromatic or heteroaromatic rings bonded to one another are intended to be encompassed within the scope of the invention.
- R 4 is a phenyl group and is substituted with two groups bonded to the C atoms adjacent to the point of attachment to the N atom of the triazole, then rotation of the phenyl may be restricted.
- the barrier of rotation is high enough that the different atropisomers may be separated and isolated.
- stereoisomer or “stereomerically pure” means one stereoisomer of a compound that is substantially free of other stereoisomers of that compound.
- a stereomerically pure compound having one chiral center will be substantially free of the mirror image enantiomer of the compound.
- a stereomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound.
- a typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more preferably greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, even more preferably greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and most preferably greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound.
- stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it.
- a bond drawn with a wavy line indicates that both stereoisomers are encompassed. This is not to be confused with a wavy line drawn perpendicular to a bond which indicates the point of attachment of a group to the rest of the molecule.
- mixtures comprising equal or unequal amounts of the enantiomers of a particular compound of the invention may be used in methods and compositions of the invention.
- These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al. (1997) Tetrahedron 33:2725; Eliel, E.
- tautomers associated with compounds of the invention are those with a pyridone group (a pyridinyl) for which hydroxypyridine is a tautomer and compounds with a ketone group with the enol tautomer. Examples of these are shown below.
- Compounds of the present disclosure include, but are not limited to, compounds of Formula I and Formula II and all pharmaceutically acceptable forms thereof.
- Pharmaceutically acceptable forms of the compounds recited herein include pharmaceutically acceptable salts, solvates, crystal forms (including polymorphs and clathrates), chelates, non-covalent complexes, prodrugs, and mixtures thereof.
- the compounds described herein are in the form of pharmaceutically acceptable salts.
- the term“compound” encompasses not only the compound itself, but also a pharmaceutically acceptable salt thereof, a solvate thereof, a chelate thereof, a non-covalent complex thereof, a prodrug thereof, and mixtures of any of the foregoing.
- the term“compound” encompasses the compound itself, pharmaceutically acceptable salts thereof, tautomers of the compound, pharmaceutically acceptable salts of the tautomers, and ester prodrugs such as (C 1 - C 4 )alkyl esters. In other embodiments, the term“compound” encompasses the compound itself, pharmaceutically acceptable salts thereof, tautomers of the compound, pharmaceutically acceptable salts of the tautomers.
- solvate refers to the compound formed by the interaction of a solvent and a compound.
- Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemi-hydrates.
- the compounds of the invention may also contain naturally occurring or unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
- the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
- Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents, e.g., assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention. For example, if a variable is said or shown to be H, this means that variable may also be deuterium (D) or tritium (T).
- Alkyl refers to a saturated branched or straight-chain monovalent hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane.
- Typical alkyl groups include, but are not limited to, methyl, ethyl, propyls such as propan-1-yl and propan-2-yl, butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, tert-butyl, and the like.
- an alkyl group comprises 1 to 20 carbon atoms.
- alkyl groups include 1 to 10 carbon atoms or 1 to 6 carbon atoms whereas in other embodiments, alkyl groups include 1 to 4 carbon atoms. In still other embodiments, an alkyl group includes 1 or 2 carbon atoms. Branched chain alkyl groups include at least 3 carbon atoms and typically include 3 to 7, or in some embodiments, 3 to 6 carbon atoms. An alkyl group having 1 to 6 carbon atoms may be referred to as a (C 1 -C 6 )alkyl group and an alkyl group having 1 to 4 carbon atoms may be referred to as a (C 1 -C 4 )alkyl.
- alkyl groups with differing numbers of carbon atoms.
- alkyl may also be used when an alkyl group is a substituent that is further substituted in which case a bond between a second hydrogen atom and a C atom of the alkyl substituent is replaced with a bond to another atom such as, but not limited to, a halogen, or an O, N, or S atom.
- a group–O-(C 1 -C 6 alkyl)-OH will be recognized as a group where an -O atom is bonded to a C 1 -C 6 alkyl group and one of the H atoms bonded to a C atom of the C 1 -C 6 alkyl group is replaced with a bond to the O atom of an–OH group.
- a group–O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl) will be recognized as a group where an -O atom is bonded to a first C 1 -C 6 alkyl group and one of the H atoms bonded to a C atom of the first C 1 -C 6 alkyl group is replaced with a bond to a second O atom that is bonded to a second C 1 -C 6 alkyl group.
- Alkenyl refers to an unsaturated branched or straight-chain hydrocarbon group having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene.
- the group may be in either the Z- or E- form (cis or trans) about the double bond(s).
- Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), and prop-2-en-2-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, and buta-1,3-dien-2-yl; and the like.
- an alkenyl group has 2 to 20 carbon atoms and in other embodiments, has 2 to 6 carbon atoms.
- An alkenyl group having 2 to 6 carbon atoms may be referred to as a (C 2 -C 6 )alkenyl group.
- Alkynyl refers to an unsaturated branched or straight-chain hydrocarbon having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne.
- Typical alkynyl groups include, but are not limited to, ethynyl; propynyl; butynyl, 2-pentynyl, 3-pentynyl, 2- hexynyl, 3-hexynyl and the like.
- an alkynyl group has 2 to 20 carbon atoms and in other embodiments, has 2 to 6 carbon atoms.
- An alkynyl group having 2 to 6 carbon atoms may be referred to as a–(C 2 -C 6 )alkynyl group.
- Alkoxy refers to a radical–OR where R represents an alkyl group as defined herein. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and the like. Typical alkoxy groups include 1 to 10 carbon atoms, 1 to 6 carbon atoms or 1 to 4 carbon atoms in the R group. Alkoxy groups that include 1 to 6 carbon atoms may be designated as–O-(C 1 -C 6 ) alkyl or as–O-(C 1 -C 6 alkyl) groups. In some embodiments, an alkoxy group may include 1 to 4 carbon atoms and may be designated as–O-(C 1 -C 4 ) alkyl or as–O-(C 1 -C 4 alkyl) groups.
- Aryl refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
- Aryl encompasses monocyclic carbocyclic aromatic rings, for example, benzene.
- Aryl also encompasses bicyclic carbocyclic aromatic ring systems where each of the rings is aromatic, for example, naphthalene.
- Aryl groups may thus include fused ring systems where each ring is a carbocyclic aromatic ring.
- an aryl group includes 6 to 10 carbon atoms. Such groups may be referred to as C 6 -C 10 aryl groups.
- Aryl does not encompass or overlap in any way with heteroaryl as separately defined below. Hence, if one or more carbocyclic aromatic rings is fused with an aromatic ring that includes at least one heteroatom, the resulting ring system is a heteroaryl group, not an aryl group, as defined herein.
- Cycloalkyl refers to a saturated cyclic alkyl group derived by the removal of one hydrogen atom from a single carbon atom of a parent cycloalkane.
- Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, and the like. Cycloalkyl groups may be described by the number of carbon atoms in the ring.
- a cycloalkyl group having 3 to 8 ring members may be referred to as a (C 3 -C 8 )cycloalkyl
- a cycloalkyl group having 3 to 7 ring members may be referred to as a (C 3 -C 7 )cycloalkyl
- a cycloalkyl group having 4 to 7 ring members may be referred to as a (C 4 -C 7 )cycloalkyl.
- the cycloalkyl group can be a
- Heterocyclyl and“heterocyclic” refer to a cyclic group that includes at least one saturated, partially unsaturated, but non-aromatic, cyclic ring.
- Heterocyclyl groups include at least one heteroatom as a ring member. Typical heteroatoms include, O, S and N and are independently chosen.
- Heterocyclyl groups include monocyclic ring systems and bicyclic ring systems.
- Bicyclic heterocyclyl groups include at least one non- aromatic ring with at least one heteroatom ring member that may be fused to a cycloalkyl ring or may be fused to an aromatic ring where the aromatic ring may be carbocyclic or may include one or more heteroatoms.
- the point of attachment of a bicyclic heterocyclyl group may be at the non-aromatic cyclic ring that includes at least one heteroatom or at another ring of the heterocyclyl group.
- a heterocyclyl group derived by removal of a hydrogen atom from one of the 9 membered heterocyclic compounds shown below may be attached to the rest of the molecule at the 5-membered ring or at the 6- membered ring.
- a heterocyclyl group includes 5 to 10 ring members of which 1, 2, 3 or 4 or 1, 2, or 3 are heteroatoms independently selected from O, S, or N. In other embodiments, a heterocyclyl group includes 3 to 7 ring members of which 1, 2, or 3 heteroatom are independently selected from O, S, or N. In such 3-7 membered heterocyclyl groups, only 1 of the ring atoms is a heteroatom when the ring includes only 3 members and includes 1 or 2 heteroatoms when the ring includes 4 members. In some embodiments, a heterocyclyl group includes 3 or 4 ring members of which 1 is a heteroatom selected from O, S, or N.
- a heterocyclyl group includes 5 to 7 ring members of which 1, 2, or 3 are heteroatoms independently selected from O, S, or N.
- Typical heterocyclyl groups include, but are not limited to, groups derived from epoxides, aziridine, azetidine, imidazolidine, morpholine, piperazine, piperidine, hexahydropyrimidine, 1,4,5,6-tetrahydropyrimidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofuran, tetrahydropyran, benzimidazolone, pyridinone, and the like.
- Heterocyclyl groups may be fully saturated, but may also include one or more double bonds.
- heterocyclyl groups include, but are not limited to, 1,2,3,6-tetrahydropyridinyl, 3,6-dihydro-2H-pyranyl, 3,4-dihydro-2H-pyranyl, 2,5- dihydro-1H-pyrolyl, 2,3-dihydro-1H-pyrolyl, 1H-azirinyl, 1,2-dihydroazetenyl, and the like.
- a saturated 5-membered hetereocycle containing one heteroatom which is a S may include the following heterocy
- Disease refers to any disease, disorder, condition, symptom, or indication.
- Halo or“halogen” refers to a fluoro, chloro, bromo, or iodo group.
- Haloalkyl refers to an alkyl group in which at least one hydrogen is replaced with a halogen.
- haloalkyl includes monohaloalkyl (alkyl substituted with one halogen atom) and polyhaloalkyl (alkyl substituted with two or more halogen atoms).
- Representative“haloalkyl” groups include difluoromethyl, 2,2,2- trifluoroethyl, 2,2,2-trichloroethyl, and the like.
- perhaloalkyl means, unless otherwise stated, an alkyl group in which each of the hydrogen atoms is replaced with a halogen atom.
- perhaloalkyl includes, but is not limited to, trifluoromethyl, pentachloroethyl, 1,1,1-trifluoro-2-bromo-2-chloroethyl, and the like.
- Heteroaryl refers to a monovalent heteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system. Heteroaryl groups typically include 5- to 14-membered, but more typically include 5- to 10-membered aromatic, monocyclic, bicyclic, and tricyclic rings containing one or more, for example, 1, 2, 3, or 4, or in certain embodiments, 1, 2, or 3, heteroatoms chosen from O, S, or N, with the remaining ring atoms being carbon. In monocyclic heteroaryl groups, the single ring is aromatic and includes at least one heteroatom.
- a monocyclic heteroaryl group may include 5 or 6 ring members and may include 1, 2, 3, or 4 heteroatoms, 1, 2, or 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom where the heteroatom(s) are independently selected from O, S, or N.
- bicyclic aromatic rings both rings are aromatic.
- bicyclic heteroaryl groups at least one of the rings must include a heteroatom, but it is not necessary that both rings include a heteroatom although it is permitted for them to do so.
- the term“heteroaryl” includes a 5- to 7- membered heteroaromatic ring fused to a carbocyclic aromatic ring or fused to another heteroaromatic ring.
- the rings are aromatic and at least one of the rings includes at least one heteroatom.
- the point of attachment may be at the ring including at least one heteroatom or at a carbocyclic ring.
- the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another.
- the total number of S and O atoms in the heteroaryl group is not more than 2.
- the total number of S and O atoms in the aromatic heterocycle is not more than 1.
- Heteroaryl does not encompass or overlap with aryl as defined above.
- heteroaryl groups include, but are not limited to, groups derived from acridine, carbazole, cinnoline, furan, imidazole, indazole, indole, indolizine, isobenzofuran, isochromene, isoindole, isoquinoline, isothiazole, 2H-benzo[d][1,2,3]triazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazo
- the heteroaryl group can be between 5 to 20 membered heteroaryl, such as, for example, a 5 to 14 membered or 5 to 10 membered heteroaryl.
- heteroaryl groups can be those derived from thiophene, pyrrole, benzothiophene, 2H- benzo[d][1,2,3]triazole benzofuran, indole, pyridine, quinoline, imidazole, benzimidazole, oxazole, tetrazole, and pyrazine.
- “Pharmaceutically acceptable” refers to generally recognized for use in animals, and more particularly in humans.
- “Pharmaceutically acceptable salt” refers to a salt of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
- Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an al
- “Pharmaceutically acceptable excipient” refers to a broad range of ingredients that may be combined with a compound or salt of the present invention to prepare a pharmaceutical composition or formulation.
- excipients include, but are not limited to, diluents, colorants, vehicles, anti-adherants, glidants, disintegrants, flavoring agents, coatings, binders, sweeteners, lubricants, sorbents, preservatives, and the like.
- Stepoisomer refers to an isomer that differs in the arrangement of the constituent atoms in space.
- Stereoisomers that are mirror images of each other and optically active are termed“enantiomers,” and stereoisomers that are not mirror images of one another and are optically active are termed“diastereomers.”
- “Subject” includes mammals and humans.
- the terms“human” and “subject” are used interchangeably herein.
- “Therapeutically effective amount” refers to the amount of a compound that, when administered to a subject for treating a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or symptom. As those skilled in the art will recognize this amount is typically not limited to a single dose, but may comprise multiple dosages over a significant period of time as required to bring about a therapeutic or prophylactic response in the subject.
- a“therapeutically effective amount” is not limited to the amount in a single capsule or tablet, but may include more than one capsule or tablet, which is the dose prescribed by a qualified physician or medical care provider.
- The“therapeutically effective amount” can vary depending on the compound, the disease, disorder, and/or symptoms of the disease or disorder, severity of the disease, disorder, and/or symptoms of the disease or disorder, the age of the subject to be treated, and/or the weight of the subject to be treated. An appropriate amount in any given instance can be readily apparent to those skilled in the art or capable of determination by routine experimentation.
- Treating” or“treatment” of any disease or disorder refers to arresting or ameliorating a disease, disorder, or at least one of the clinical symptoms of a disease or disorder, reducing the risk of acquiring a disease, disorder, or at least one of the clinical symptoms of a disease or disorder, reducing the development of a disease, disorder or at least one of the clinical symptoms of the disease or disorder, or reducing the risk of developing a disease or disorder or at least one of the clinical symptoms of a disease or disorder.“Treating” or“treatment” also refers to inhibiting the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both, or inhibiting at least one physical parameter which may not be discernible to the subject. Further,“treating” or“treatment” refers to delaying the onset of the disease or disorder or at least symptoms thereof in a subject which may be exposed to or predisposed to a disease or disorder even though that subject does not
- the invention provides a compound of Formula I or Formula II:
- R 1 is a 3-, 4-, 5-, 6-, 7-, or 8-membered saturated or partially saturated heterocyclic group that includes 1, 2, or 3 heteroatoms independently selected from N, O, or S that is unsubstituted or is substituted with 1, 2, or 3 R 1a substituents;
- R 1a in each instance is independently selected from -F, -Cl, -Br, -I, -C1-C6 alkyl, - C 1 -C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -CN, -OH, -O-(C 1 - C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -C 2 -C 6 alkenyl, -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl)-OH, -O-(C 1 -C 6 haloalkyl)
- R 1a’ is in each instance independently selected from -F, -Cl, -Br, -I, -C 1 -C 6 alkyl, - C 1 -C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, C 3 -C 8 cycloalkyl -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), - CN, -OH, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -C 2 -C 6 alkenyl, -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl)- OH, -
- R 2 is selected from -H, or C 1 -C 4 alkyl or is absent in the compounds of Formula II;
- R 3 is selected from an unsubstituted C 1 -C 10 alkyl, a C 1 -C 10 alkyl substituted with 1, 2, or 3 R 3a substituents, a group of formula -(CR 3b R 3c )-Q, a group of formula
- R 3b and R 3c are independently selected from–H, -F, -Cl, -CN, -C 1 -C 6 alkyl, -C 1 - C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, -OH, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or–N(C 1 -C 6 alkyl) 2 ;
- R 3d and R 3e are independently selected from–H, -F, -Cl, -CN, -C 1 -C 6 alkyl, -C 1 - C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, -OH, -(C 1 -C 6 alkyl)-OH, -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl)-phenyl, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O- (C 1 -C 6 perhaloalkyl), -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -NH 2 , -
- R 3f and R 3g are independently selected from–H, -F, -Cl, -CN, -C 1 -C 6 alkyl, -C 1 - C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, -OH, -(C 1 -C 6 alkyl)-OH, -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -O-(C 2 -C 6 alkenyl), -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or–N(
- Q is a monocyclic or bicyclic C 6 -C 10 aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a C 3 -C 8 cycloalkyl group, a 3 to 10 membered heterocyclyl group containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, wherein the C 6 -C 10 aryl, the heteroaryl, the cycloalkyl, and the heterocyclyl Q groups are unsubstituted or are substituted with 1, 2, 3, or 4 R Q substituents; and further wherein the Q heterocyclyl group may additionally be substituted with 1 or 2 oxo substituents, and the Q heteroaryl group may include an N-oxide if the heteroaryl includes a N heteroatom; R Q in each instance is independently selected from -F, -Cl, -Br, -I, -CN, -
- R 4 is selected from a monocyclic or bicyclic C 6 -C 10 aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a monocyclic or bicyclic heterocyclyl group with 5 to 10 ring members containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S, a monocyclic 3-6 membered cycloalkyl group, or a straight or branched chain C 1 - C 6 alkyl group, wherein the C 6 -C 10 aryl, the heteroaryl, and the heterocyclyl R 4 group are unsubstituted or are substituted with 1, 2, 3, or 4 R 4a substituents, and further wherein the cycloalkyl R 4 group is unsubstituted or is substituted with 1, 2, 3, or 4 R 4b substituents, and further wherein the straight or branched chain C 1 -C 6 alkyl R 4
- R 1a substituents on adjacent carbon atoms or on an adjacent carbon atom and an adjacent N atom of a 5- or 6-membered heterocyclic R 1 group join to form a 6 membered ring that may be saturated, partially saturated, or aromatic and may include 0, 1, or 2 N atoms and may further optionally be substituted with 1 or 2 R 1a’ substituents and may include an oxo substituent if the ring is not an aromatic ring; or
- R 1a substituents on adjacent carbon atoms or on an adjacent carbon atom and an adjacent N atom of a 5- or 6-membered heterocyclic R 1 group join to form a 5 membered ring that may be saturated, partially saturated, or aromatic and may include 0, 1, or 2 heteroatoms selected from N, O, or S and may further optionally be substituted with 1 or 2 R 1a’ substituent and may include an oxo substituent if the ring is not an aromatic ring.
- the invention provides a compound of Formula I or Formula II:
- R 1 is a 3-, 4-, 5-, 6-, 7-, or 8-membered saturated or partially saturated heterocyclic group that includes 1, 2, or 3 heteroatoms independently selected from N, O, or S that is unsubstituted or is substituted with 1, 2, or 3 R 1a substituents;
- R 1a in each instance is independently selected from -F, -Cl, -Br, -I, -C 1 -C 6 alkyl, - C 1 -C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -CN, -OH, -O-(C 1 - C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -C 2 -C 6 alkenyl, -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl)-OH, -O-(C 1 -C 6 haloalkyl
- R 1a’ is in each instance independently selected from -F, -Cl, -Br, -I, -C 1 -C 6 alkyl, - C 1 -C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, C 3 -C 8 cycloalkyl -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), - CN, -OH, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -C 2 -C 6 alkenyl, -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl)- OH, -
- R 2 is selected from -H, or C 1 -C 4 alkyl or is absent in the compounds of Formula II;
- R 3 is selected from an unsubstituted C 1 -C 10 alkyl, a C 1 -C 10 alkyl substituted with 1, 2, or 3 R 3a substituents, a group of formula -(CR 3b R 3c )-Q, a group of formula
- R 3a in each instance is independently selected from -F, -Cl, -CN, -OH, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -NH 2 , -NH(C 1 -C 6 alkyl), or–N(C 1 - C 6 alkyl) 2 ;
- R 3b and R 3c are independently selected from–H, -F, -Cl, -CN, -C 1 -C 6 alkyl, -C 1 - C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, -OH, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or–N(C 1 -C 6 alkyl) 2 ;
- R 3d and R 3e are independently selected from–H, -F, -Cl, -CN, -C 1 -C 6 alkyl, -C 1 - C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, -OH, -(C 1 -C 6 alkyl)-OH, -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl)-phenyl, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O- (C 1 -C 6 perhaloalkyl), -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -NH 2 , -
- R 3f and R 3g are independently selected from–H, -F, -Cl, -CN, -C 1 -C 6 alkyl, -C 1 - C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, -OH, -(C 1 -C 6 alkyl)-OH, -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -O-(C 2 -C 6 alkenyl), -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or–N(
- Q is a monocyclic or bicyclic C 6 -C 10 aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a C 3 -C 8 cycloalkyl group, a 3 to 10 membered heterocyclyl group containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, wherein the C 6 -C 10 aryl, the heteroaryl, the cycloalkyl, and the heterocyclyl Q groups are unsubstituted or are substituted with 1, 2, 3, or 4 R Q substituents; and further wherein the Q heterocyclyl group may additionally be substituted with 1 or 2 oxo substituents, and the Q heteroaryl group may include an N-oxide if the heteroaryl includes a N heteroatom;
- R 4 is selected from a monocyclic or bicyclic C 6 -C 10 aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a monocyclic or bicyclic heterocyclyl group with 5 to 10 ring members containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S, or a monocyclic 3-6 membered cycloalkyl group, wherein the C 6 -C 10 aryl, the heteroaryl, the heterocyclyl, and the cycloalkyl R 4 group are unsubstituted or are substituted with 1, 2, 3, or 4 R 4a substituents; and
- dioxotetrahydrothiophenyl morpholinyl, dioxolanyl, or tetrahydrothiophenyl, any of which may unsubstituted or substituted with 1, 2, or 3 independently selected R 1a substituents.
- R 3d and R 3e are independently selected from–H, -C 1 -C 6 alkyl, -(C 1 -C 6 alkyl)-OH, or -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl); and R 3f and R 3g are independently selected from–H, -F, -C 1 -C 6 alkyl, -C 1 -C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, -OH, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), or -O-(C 2 -C 6 alkenyl).
- R 3d and R 3e are independently selected from–H, or -C 1 -C 6 alkyl
- R 3f and R 3g are independently selected from–H, -C 1 -C 6 alkyl, -OH, or -O-(C 1 -C 6 alkyl).
- the pharmaceutically acceptable salt thereof the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof.
- R 1 is as defined in embodiment 8; X is selected from CH or N;
- Z is selected from CH or N
- R 3d and R 3e are independently selected from–H, -C 1 -C 6 alkyl, -(C 1 -C 6 alkyl)-OH, or -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl); and
- R 3f and R 3g are independently selected from–H, -F, -C 1 -C 6 alkyl, -C 1 -C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, -OH, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), or -O-(C 2 -C 6 alkenyl).
- Q is a phenyl group or a monocyclic heteroaryl group with 6 ring members containing 1 or 2 N heteroatoms, wherein the phenyl and the monocyclic heteroaryl Q groups are unsubstituted or are substituted with 1, 2, or 3 R Q substituent;
- R Q is independently selected from -F, -Cl, -Br, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -(C 1 -C 6 alkyl)-NH 2 or alkyl).
- R 3d and R 3e are independently selected from–H, -C 1 -C 6 alkyl, or -(C 1 -C 6 alkyl)- OH;
- R 3f and R 3g are independently selected from–H, -C 1 -C 6 alkyl, -OH, or -O-(C 1 -C 6 alkyl).
- R 1 is as defined in embodiment 8;
- X is selected from CH or N;
- Z is selected from CH or N
- R 3h is independently selected from -OH, or -O-(C 1 -C 6 alkyl);
- the subscript p is selected from 0, 1, 2, or 3;
- Q is a phenyl group or a monocyclic heteroaryl group with 6 ring members containing 1 or 2 N heteroatoms, wherein the phenyl and the monocyclic heteroaryl Q groups are unsubstituted or are substituted with 1, 2, or 3 R Q substituent;
- R Q is independently selected from -F, -Cl, -Br, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -(C 1 -C 6 alkyl)-NH 2 or alkyl).
- Q is a phenyl, a pyrimidinyl, a pyridinyl, or a pyrazinyl any of which are unsubstituted or are substituted with 1, 2, or 3 R Q substituent.
- X is N
- Q is a phenyl, a pyrimidinyl, a pyridinyl, or a pyrazinyl any of which are unsubstituted or are substituted with 1, 2, or 3 R Q substituent.
- dioxotetrahydrothiophenyl morpholinyl, dioxolanyl, or tetrahydrothiophenyl, any of which may unsubstituted or substituted with 1, 2, or 3 independently selected R 1a substituents.
- a pharmaceutical composition comprising the compound of any one of embodiments 1-92 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, and at least one pharmaceutically acceptable excipient.
- a pharmaceutical composition comprising the compound of any one of embodiments 1-92 or the pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.
- a pharmaceutical composition comprising the compound of any one of embodiments 1-92 and at least one pharmaceutically acceptable excipient.
- a pharmaceutical composition comprising the pharmaceutically acceptable salt of the compound of any one of embodiments 1-92 and at least one pharmaceutically acceptable excipient.
- composition of any one of embodiments 93- 96 further comprising a therapeutic agent selected from an ⁇ -blocker, a ⁇ -blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calcium channel blocker, a diuretic, an inhibitor of the funny current, a myosin activator, or a neutral endopeptidase (NEP) inhibitor.
- ACE angiotensin converting enzyme
- ARB angiotensin-receptor blocker
- NEP neutral endopeptidase
- ACE angiotensin converting enzyme
- ARB angiotensin-receptor blocker
- a method of treating a cardiovascular condition comprising: administering to a subject an effective amount of the compound of any one of embodiments 1-92 or the pharmaceutically acceptable salt thereof, the stereoisomer of any of the foregoing, or the mixture thereof, or the pharmaceutical composition of any one of embodiments 93-96.
- a method of improving cardiac contractility in a subject suffering from a cardiovascular condition comprising: administering to the subject an effective amount of the compound of any one of embodiments 1-92 or the pharmaceutically acceptable salt thereof, the stereoisomer of any of the foregoing, or the mixture thereof, or the pharmaceutical composition of any one of embodiments 93-96, wherein cardiac contractility is improved in the subject after administration.
- a method of increasing ejection fraction in a subject suffering from a cardiovascular condition comprising: administering to the subject an effective amount of the compound of any one of embodiments 1-92 or the
- a method of treating a condition in a subject where it is desired to activate the APJ Receptor comprising: administering to the subject an effective amount of the compound of any one of embodiments 1-92 or the
- the method includes administering at least one additional therapeutic agent to the subject, wherein the additional therapeutic agent is selected from an ⁇ -blocker, a ⁇ -blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calcium channel blocker, a diuretic, an inhibitor of the funny current, a myosin activator, or a neutral endopeptidase (NEP) inhibitor.
- the additional therapeutic agent is selected from an ⁇ -blocker, a ⁇ -blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calcium channel blocker, a diuretic, an inhibitor of the funny current, a myosin activator, or a neutral endopeptidase (NEP) inhibitor.
- ACE angiotensin converting enzyme
- ARB angiotensin-receptor blocker
- NEP neutral endopeptidase
- the method includes administering at least one additional therapeutic agent to the subject, wherein the additional therapeutic agent is selected from an angiotensin converting enzyme (ACE) inhibitor or an angiotensin-receptor blocker (ARB).
- ACE angiotensin converting enzyme
- ARB angiotensin-receptor blocker
- embodiment 123 further comprising a therapeutic agent selected from an ⁇ -blocker, a ⁇ -blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calcium channel blocker, a diuretic, an inhibitor of the funny current, a myosin activator, or a neutral endopeptidase (NEP) inhibitor.
- a therapeutic agent selected from an ⁇ -blocker, a ⁇ -blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calcium channel blocker, a diuretic, an inhibitor of the funny current, a myosin activator, or a neutral endopeptidase (NEP) inhibitor.
- ACE angiotensin converting enzyme
- ARB angiotensin-receptor blocker
- NEP neutral endopeptidase
- embodiment 123 further comprising a therapeutic agent selected from an angiotensin converting enzyme (ACE) inhibitor or an angiotensin- receptor blocker (ARB).
- ACE angiotensin converting enzyme
- ARB angiotensin- receptor blocker
- a treatment regimen for a cardiovascular disease comprising: the compound of any one of embodiments 1-92 or the pharmaceutically acceptable salt thereof, the stereoisomer of any of the foregoing, or the mixture thereof.
- a therapeutic agent selected from an ⁇ -blocker, a ⁇ -blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calcium channel blocker, a diuretic, an inhibitor of the funny current, a myosin activator, or a neutral endopeptidase (NEP) inhibitor.
- ACE angiotensin converting enzyme
- ARB angiotensin-receptor blocker
- NEP neutral endopeptidase
- a therapeutic agent selected from an angiotensin converting enzyme (ACE) inhibitor or an angiotensin-receptor blocker (ARB).
- ACE angiotensin converting enzyme
- ARB angiotensin-receptor blocker
- kits comprising: the compound of any one of embodiments 1-91 or the pharmaceutically acceptable salt thereof, the stereoisomer of any of the foregoing, or the mixture thereof.
- kits of embodiment 138 wherein the kit further comprises a therapeutic agent selected from an ⁇ -blocker, a ⁇ -blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calcium channel blocker, a diuretic, an inhibitor of the funny current, a myosin activator, or a neutral endopeptidase (NEP) inhibitor.
- a therapeutic agent selected from an ⁇ -blocker, a ⁇ -blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calcium channel blocker, a diuretic, an inhibitor of the funny current, a myosin activator, or a neutral endopeptidase (NEP) inhibitor.
- ACE angiotensin converting enzyme
- ARB angiotensin-receptor blocker
- NEP neutral endopeptidase
- kits of embodiment 138 wherein the kit further comprises a therapeutic agent selected from an angiotensin converting enzyme (ACE) inhibitor or an angiotensin-receptor blocker (ARB).
- ACE angiotensin converting enzyme
- ARB angiotensin-receptor blocker
- the invention provides a compound of Formula V, a salt thereof, a tautomer thereof, or a salt of the tautomer:
- R 1 is a 3-, 4-, 5-, 6-, 7-, or 8-membered saturated or partially saturated heterocyclic group that includes 1, 2, or 3 heteroatoms independently selected from N, O, or S that is unsubstituted or is substituted with 1, 2, or 3 R 1a substituents;
- R 1a in each instance is independently selected from -F, -Cl, -Br, -I, -C 1 -C 6 alkyl, - C 1 -C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -CN, -OH, -O-(C 1 - C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -C 2 -C 6 alkenyl, -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl)-OH, -O-(C 1 -C 6 haloalkyl
- R 1a’ is in each instance independently selected from -F, -Cl, -Br, -I, -C 1 -C 6 alkyl, - C 1 -C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, C 3 -C 8 cycloalkyl -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), - CN, -OH, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -C 2 -C 6 alkenyl, -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl)- OH, -
- R 3 is selected from an unsubstituted C 1 -C 10 alkyl, a C 1 -C 10 alkyl substituted with 1, 2, or 3 R 3a substituents, a group of formula -(CR 3b R 3c )-Q, a group of formula
- R 3a in each instance is independently selected from -F, -Cl, -CN, -OH, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -NH 2 , -NH(C 1 -C 6 alkyl), or–N(C 1 - C 6 alkyl) 2 ;
- R 3b and R 3c are independently selected from–H, -F, -Cl, -CN, -C 1 -C 6 alkyl, -C 1 - C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, -OH, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or–N(C 1 -C 6 alkyl) 2 ;
- R 3d and R 3e are independently selected from–H, -F, -Cl, -CN, -C 1 -C 6 alkyl, -C 1 - C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, -OH, -(C 1 -C 6 alkyl)-OH, -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl)-phenyl, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O- (C 1 -C 6 perhaloalkyl), -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -NH 2 , -
- R 3f and R 3g are independently selected from–H, -F, -Cl, -CN, -C 1 -C 6 alkyl, -C 1 - C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, -OH, -(C 1 -C 6 alkyl)-OH, -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -O-(C 2 -C 6 alkenyl), -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or–N(
- Q is a monocyclic or bicyclic C 6 -C 10 aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a C 3 -C 8 cycloalkyl group, a 3 to 10 membered heterocyclyl group containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, wherein the C 6 -C 10 aryl, the heteroaryl, the cycloalkyl, and the heterocyclyl Q groups are unsubstituted or are substituted with 1, 2, 3, or 4 R Q substituents; and further wherein the Q heterocyclyl group may additionally be substituted with 1 or 2 oxo substituents, and the Q heteroaryl group may include an N-oxide if the heteroaryl includes a N heteroatom;
- R 4 is selected from a monocyclic or bicyclic C 6 -C 10 aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a monocyclic or bicyclic heterocyclyl group with 5 to 10 ring members containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S, or a monocyclic 3-6 membered cycloalkyl group, wherein the C 6 -C 10 aryl, the heteroaryl, the heterocyclyl, and the cycloalkyl R 4 group are unsubstituted or are substituted with 1, 2, 3, or 4 R 4a substituents; and
- R 1 is a 3-, 4-, 5-, 6-, 7-, or 8-membered saturated or partially saturated heterocyclic group that includes 1, 2, or 3 heteroatoms independently selected from N, O, or S that is unsubstituted or is substituted with 1, 2, or 3 R 1a substituents;
- R 1a in each instance is independently selected from -F, -Cl, -Br, -I, -C 1 -C 6 alkyl, - C 1 -C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -CN, -OH, -O-(C 1 - C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -C 2 -C 6 alkenyl, -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl)-OH, -O-(C 1 -C 6 haloalkyl
- R 3 is selected from an unsubstituted C 1 -C 10 alkyl, a C 1 -C 10 alkyl substituted with 1, 2, or 3 R 3a substituents, a group of formula -(CR 3b R 3c )-Q, a group of formula
- R 3a in each instance is independently selected from -F, -Cl, -CN, -OH, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -NH 2 , -NH(C 1 -C 6 alkyl), or–N(C 1 - C 6 alkyl) 2 ;
- R 3b and R 3c are independently selected from–H, -F, -Cl, -CN, -C 1 -C 6 alkyl, -C 1 - C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, -OH, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or–N(C 1 -C 6 alkyl) 2 ;
- R 3d and R 3e are independently selected from–H, -F, -Cl, -CN, -C 1 -C 6 alkyl, -C 1 - C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, -OH, -(C 1 -C 6 alkyl)-OH, -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl)-phenyl, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O- (C 1 -C 6 perhaloalkyl), -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -NH 2 , -
- R 3f and R 3g are independently selected from–H, -F, -Cl, -CN, -C 1 -C 6 alkyl, -C 1 - C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, -OH, -(C 1 -C 6 alkyl)-OH, -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -O-(C 2 -C 6 alkenyl), -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or–N(
- Q is a monocyclic or bicyclic C 6 -C 10 aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a C 3 -C 8 cycloalkyl group, a 3 to 10 membered heterocyclyl group containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, wherein the C 6 -C 10 aryl, the heteroaryl, the cycloalkyl, and the heterocyclyl Q groups are unsubstituted or are substituted with 1, 2, 3, or 4 R Q substituents; and further wherein the Q heterocyclyl group may additionally be substituted with 1 or 2 oxo substituents, and the Q heteroaryl group may include an N-oxide if the heteroaryl includes a N heteroatom;
- R 4 is selected from a monocyclic or bicyclic C 6 -C 10 aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a monocyclic or bicyclic heterocyclyl group with 5 to 10 ring members containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S, a monocyclic 3-6 membered cycloalkyl group, or a straight or branched chain C 1 - C 6 alkyl group, wherein the C 6 -C 10 aryl, the heteroaryl, and the heterocyclyl R 4 group are unsubstituted or are substituted with 1, 2, 3, or 4 R 4a substituents, and further wherein the cycloalkyl R 4 group is unsubstituted or is substituted with 1, 2, 3, or 4 R 4b substituents, and further wherein the straight or branched chain C 1 -C 6 alkyl R 4
- the provides a method for preparing a compound of Formula VI, a salt thereof, a tautomer thereof, or a salt of the tautomer:
- the method comprising: a) cyclizing a compound of Formula V, a salt thereof, a tautomer thereof, or a salt of the tautomer in the presence of an acid or a base to form the compound of Formula VI, the salt thereof, the tautomer thereof, or the salt of the tautomer,
- R 1 is a 3-, 4-, 5-, 6-, 7-, or 8-membered saturated or partially saturated heterocyclic group that includes 1, 2, or 3 heteroatoms independently selected from N, O, or S that is unsubstituted or is substituted with 1, 2, or 3 R 1a substituents;
- R 1a in each instance is independently selected from -F, -Cl, -Br, -I, -C 1 -C 6 alkyl, - C 1 -C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -CN, -OH, -O-(C 1 - C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -C 2 -C 6 alkenyl, -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl)-OH, -O-(C 1 -C 6 haloalkyl
- R 1a’ is in each instance independently selected from -F, -Cl, -Br, -I, -C 1 -C 6 alkyl, - C 1 -C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, C 3 -C 8 cycloalkyl -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), - CN, -OH, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -C 2 -C 6 alkenyl, -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl)- OH, -
- R 3 is selected from an unsubstituted C 1 -C 10 alkyl, a C 1 -C 10 alkyl substituted with 1, 2, or 3 R 3a substituents, a group of formula -(CR 3b R 3c )-Q, a group of formula
- R 3a in each instance is independently selected from -F, -Cl, -CN, -OH, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -NH 2 , -NH(C 1 -C 6 alkyl), or–N(C 1 - C 6 alkyl) 2 ;
- R 3b and R 3c are independently selected from–H, -F, -Cl, -CN, -C 1 -C 6 alkyl, -C 1 - C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, -OH, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or–N(C 1 -C 6 alkyl) 2 ;
- R 3d and R 3e are independently selected from–H, -F, -Cl, -CN, -C 1 -C 6 alkyl, -C 1 - C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, -OH, -(C 1 -C 6 alkyl)-OH, -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl)-phenyl, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O- (C 1 -C 6 perhaloalkyl), -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -NH 2 , -
- R 3f and R 3g are independently selected from–H, -F, -Cl, -CN, -C 1 -C 6 alkyl, -C 1 - C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, -OH, -(C 1 -C 6 alkyl)-OH, -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -O-(C 2 -C 6 alkenyl), -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or–N(
- Q is a monocyclic or bicyclic C 6 -C 10 aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a C 3 -C 8 cycloalkyl group, a 3 to 10 membered heterocyclyl group containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, wherein the C 6 -C 10 aryl, the heteroaryl, the cycloalkyl, and the heterocyclyl Q groups are unsubstituted or are substituted with 1, 2, 3, or 4 R Q substituents; and further wherein the Q heterocyclyl group may additionally be substituted with 1 or 2 oxo substituents, and the Q heteroaryl group may include an N-oxide if the heteroaryl includes a N heteroatom;
- R 4 is selected from a monocyclic or bicyclic C 6 -C 10 aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a monocyclic or bicyclic heterocyclyl group with 5 to 10 ring members containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S, or a monocyclic 3-6 membered cycloalkyl group, wherein the C 6 -C 10 aryl, the heteroaryl, the heterocyclyl, and the cycloalkyl R 4 group are unsubstituted or are substituted with 1, 2, 3, or 4 R 4a substituents; and R 4a in each instance is independently selected from -F, -Cl, -Br, -I, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 haloalkyl, -C 1 -C 6 perhalo
- heating the compound of Formula V, the salt thereof, the tautomer thereof, or the salt of the tautomer comprises heating the compound to a temperature of from 50 °C to 100 °C.
- heating the compound of Formula V, the salt thereof, the tautomer thereof, or the salt of the tautomer comprises heating the compound to a temperature of from 60 °C to 85 °C.
- the provides a method for preparing a compound of Formula VI, a salt thereof, a tautomer thereof, or a salt of the tautomer:
- R 1 is a 3-, 4-, 5-, 6-, 7-, or 8-membered saturated or partially saturated heterocyclic group that includes 1, 2, or 3 heteroatoms independently selected from N, O, or S that is unsubstituted or is substituted with 1, 2, or 3 R 1a substituents;
- R 1a in each instance is independently selected from -F, -Cl, -Br, -I, -C 1 -C 6 alkyl, - C 1 -C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -CN, -OH, -O-(C 1 - C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -C 2 -C 6 alkenyl, -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl)-OH, -O-(C 1 -C 6 haloalkyl
- R 1a’ is in each instance independently selected from -F, -Cl, -Br, -I, -C 1 -C 6 alkyl, - C 1 -C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, C 3 -C 8 cycloalkyl -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), - CN, -OH, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -C 2 -C 6 alkenyl, -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl)- OH, -
- R 3 is selected from an unsubstituted C 1 -C 10 alkyl, a C 1 -C 10 alkyl substituted with 1, 2, or 3 R 3a substituents, a group of formula -(CR 3b R 3c )-Q, a group of formula
- R 3a in each instance is independently selected from -F, -Cl, -CN, -OH, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -NH 2 , -NH(C 1 -C 6 alkyl), or–N(C 1 - C 6 alkyl) 2 ;
- R 3b and R 3c are independently selected from–H, -F, -Cl, -CN, -C 1 -C 6 alkyl, -C 1 - C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, -OH, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or–N(C 1 -C 6 alkyl) 2 ;
- R 3d and R 3e are independently selected from–H, -F, -Cl, -CN, -C 1 -C 6 alkyl, -C 1 - C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, -OH, -(C 1 -C 6 alkyl)-OH, -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl)-phenyl, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O- (C 1 -C 6 perhaloalkyl), -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -NH 2 , -
- R 3f and R 3g are independently selected from–H, -F, -Cl, -CN, -C 1 -C 6 alkyl, -C 1 - C 6 haloalkyl, -C 1 -C 6 perhaloalkyl, -OH, -(C 1 -C 6 alkyl)-OH, -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -O-(C 2 -C 6 alkenyl), -O-(C 1 -C 6 alkyl)-OH, -O-(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or–N(
- Q is a monocyclic or bicyclic C 6 -C 10 aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a C 3 -C 8 cycloalkyl group, a 3 to 10 membered heterocyclyl group containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, wherein the C 6 -C 10 aryl, the heteroaryl, the cycloalkyl, and the heterocyclyl Q groups are unsubstituted or are substituted with 1, 2, 3, or 4 R Q substituents; and further wherein the Q heterocyclyl group may additionally be substituted with 1 or 2 oxo substituents, and the Q heteroaryl group may include an N-oxide if the heteroaryl includes a N heteroatom;
- R 4 is selected from a monocyclic or bicyclic C 6 -C 10 aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a monocyclic or bicyclic heterocyclyl group with 5 to 10 ring members containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S, a monocyclic 3-6 membered cycloalkyl group, or a straight or branched chain C 1 - C 6 alkyl group, wherein the C 6 -C 10 aryl, the heteroaryl, and the heterocyclyl R 4 group are unsubstituted or are substituted with 1, 2, 3, or 4 R 4a substituents, and further wherein the cycloalkyl R 4 group is unsubstituted or is substituted with 1, 2, 3, or 4 R 4b substituents, and further wherein the straight or branched chain C 1 -C 6 alkyl R 4
- heating the compound of Formula V, the salt thereof, the tautomer thereof, or the salt of the tautomer comprises heating the compound to a temperature of from 50 °C to 100 °C.
- heating the compound of Formula V, the salt thereof, the tautomer thereof, or the salt of the tautomer comprises heating the compound to a temperature of from 60 °C to 85 °C.
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US9573936B2 (en) * | 2015-05-20 | 2017-02-21 | Amgen Inc. | Triazole agonists of the APJ receptor |
WO2018093579A1 (en) | 2016-11-16 | 2018-05-24 | Amgen Inc. | Triazole phenyl compounds as agonists of the apj receptor |
EP3541804A1 (en) | 2016-11-16 | 2019-09-25 | Amgen Inc. | Cycloalkyl substituted triazole compounds as agonists of the apj receptor |
WO2018097944A1 (en) * | 2016-11-16 | 2018-05-31 | Amgen Inc. | Triazole furan compounds as agonists of the apj receptor |
EP3541805B1 (en) | 2016-11-16 | 2020-10-14 | Amgen Inc. | Heteroaryl-substituted triazoles as apj receptor agonists |
WO2018093580A1 (en) * | 2016-11-16 | 2018-05-24 | Amgen Inc. | Triazole pyridyl compounds as agonists of the apj receptor |
MA46824A (en) | 2016-11-16 | 2019-09-25 | Amgen Inc | ALKYL SUBSTITUTED TRIAZOLE COMPOUNDS AS APJ RECEPTOR AGONISTS |
EP3704122B1 (en) * | 2017-11-03 | 2021-09-01 | Amgen Inc. | Fused triazole agonists of the apj receptor |
WO2019213006A1 (en) | 2018-05-01 | 2019-11-07 | Amgen Inc. | Substituted pyrimidinones as agonists of the apj receptor |
CN117417325A (en) * | 2023-12-19 | 2024-01-19 | 药康众拓(北京)医药科技有限公司 | Deuterated 1,2, 4-triazole Apelin receptor agonist drug and application |
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